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Drug safety & pharmacovigilance, Phase IV, post marketing surveillance & toxicology glossary & taxonomy
Evolving Terminologies for Emerging Technologies
Comments? Questions? Revisions?  Mary Chitty 
mchitty@healthtech.com
Last revised April 24, 2014
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adverse drug event ADE:  Recently, another more inclusive term, Adverse Drug Event (ADE) has come into use. According to Bates et al, the term ADE, defined as an injury resulting from medical intervention related to a drug, is preferred since it is more comprehensive and clinically significant than the ADR. (JAMA 1995;274:29- 34). Saeed A Khan, "Drug Interaction or Adverse Drug Reaction? Confusing Terms", British Medical Journal 10 July, 1998 http://bmj.com/cgi/eletters/316/7149/1930
Related terms: adverse drug reaction ADR, drug interaction  

adverse event terminology, Norman GoldFarb 2012 Journal of Clinical Research Best Practices http://firstclinical.com/journal/2012/1207_Adverse.pdf 

adverse drug reaction ADR:  ADRs may include drug interactions as one of many causes but the reverse is not true. The reader is cautioned regarding usage of drug reaction terms as multiple nearly- similar terms of varying granularity abound. .. "An adverse reaction to a drug has been defined as any noxious or unintended reaction to a drug that is administered in standard doses by the proper route for the purpose of prophylaxis, diagnosis, or treatment(2). However, WHO's original definition of ADR excluded therapeutic failures, intentional and accidental poisoning and drug abuse, as well as adverse events due to medication errors such as drug administration or non- compliance(1) ... Due to non- uniform usage of these terms, it is sometimes difficult to compare various studies and derive incidence rates, etc. for ADRs, and Drug Interactions. Saeed A Khan, "Drug Interaction or Adverse Drug Reaction? Confusing Terms", British Medical Journal 10 July, 1998 http://bmj.com/cgi/eletters/316/7149/1930

We define an adverse drug reaction as "an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product." Such reactions are currently reported by use of WHO's Adverse Reaction Terminology, which will eventually become a subset of the International Classification of Diseases. Adverse drug reactions are classified into six types (with mnemonics): dose-related (Augmented), non-dose-related (Bizarre), dose-related and time-related (Chronic), time-related (Delayed), withdrawal (End of use), and failure of therapy (Failure).  Edwards, IR; Aronson JK,  Adverse Drug Reactions, Definitions, Diagnosis and Management, Lancet 356(9237): 1255- 1259, 2000 Oct 7

WHO, Adverse Reaction Terminology, 2009 http://www.umc-products.com/graphics/3036.pdf 
Wikipedia http://en.wikipedia.org/wiki/Adverse_drug_reaction 

Related terms: adverse drug event ADE, drug interaction  

Ames test: This test for genotoxicity, developed in the 1970s, determines the reversion of a mutant his gene in Salmonella typhimurium when exposed to a genotoxic agent that causes base changes affecting the mutant gene.

antedrugs: The antedrug concept was introduced by Lee and Soliman in 1982 in designing potent, yet safer locally active anti-inflammatory steroids. Antedrug  is defined as an active synthetic derivative that is designed to undergo biotransformation to the readily excretable inactive form upon entry in the systemic circulation, thus  minimizing systemic side effects and increasing the therapeutic indices  MO Khan et al   Antedrugs: an approach to safer drugs, Current Med Chem 2005;12(19): 2227-2239

Bayesian clinical forecasting: Clinical trials

biochemical toxicology: Of particular interest [to the Journal of Biochemical and Molecular toxicology] are aspects of molecular biology related to biochemical toxicology. These include studies of the expression of genes related to detoxication and activation enzymes, toxicants with modes of action involving effects on nucleic acids, gene expression and protein synthesis, and the toxicity of products derived from biotechnology. Journal of Biochemical and Molecular Toxicology, Wiley Periodicals http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1099-0461/homepage/ProductInformation.html 

The Division of Biochemical Toxicology conducts fundamental and applied research specifically designed to define the biological mechanisms of action underlying the toxicity of products regulated by, or of interest to, the Centers of the Food and Drug Administration (FDA). This research centers on quantifying the toxicities and carcinogenic risks associated with specific chemicals and gene-nutrient interactions and the introduction of new techniques to assess toxicities and carcinogenic risks. The risk-assessment research is firmly rooted in mechanistic studies focused on the understanding of toxicological endpoints, an approach that allows greater confidence in the subsequent risk assessments. Research within the Division capitalizes on scientific knowledge in the areas of biochemistry, organic chemistry, analytical chemistry, cellular and molecular biology, nutritional biochemistry, toxicology, phototoxicology, and pharmacology. A major emphasis within the Division continues to be conducting research on compounds nominated by FDA for evaluation by the National Institute of Environmental Health Sciences/National Toxicology Program (NIEHS/NTP).   http://www.fda.gov/aboutfda/centersoffices/oc/officeofscientificandmedicalprograms/nctr/whatwedo/researchdivisions/ucm078482.htm 

cardiotoxicity:
At least 50 companies have a claimed product or service relevant to cardiotoxicity screening, of which 29 have some clear focus on proarrhythmic cardiotoxicity or ion channel screening. ... Ion currents across a cardiac myocyte cell membrane cause a sequence of voltage changes known as the action potential, which is the basis of the heartbeat.  Drug-mediated interference with one or more of the ion channels that give rise to the action potential may cause potentially lethal arrhythmias. This could be brought about by direct binding of drug to ion channel proteins, or by indirect interference with ion channel function. The clinical outcome of drug-ion channel interactions could be potentiated by a variety of predisposing factors, such as concurrent disease, medication, genetic variations, age, and gender. Insight Pharma Reports, Cardiotoxicity issues, technologies and solutions for the future, 2008 

Cardiotoxicity is one of the major forms of toxicity seen in drugs and it accounts for most drug recalls and delays experienced in regulatory approvals. While improvements in experimental and clinical trial design have helped with better detection of cardiac toxicity in drug candidates, the problem still persists and often goes unnoticed until the compound is further along in development or has reached the market. 

computational toxicology: EPA’s Computational Toxicology Research Program is intended to provide innovative solutions to a number of persistent and pervasive issues facing EPAs regulatory programs. The vision of the program is an EPA that efficiently characterizes exposure, hazard, and risk through the broad use of modern biological tools, information technologies, and computational models. National Center for Computational Toxicology, US EPA, 2008  http://www.epa.gov/ncct/comptoxfactsheet.html 

disproportionate drug metabolite: A metabolite present only in humans or present at higher plasma concentrations in humans than in the animals used in Nonclinical studies. In general, these metabolites are of interest if they account for plasma levels greater than 10 percent of parent systemic exposure, measured as area under the curve (AUC) at steady. state  Glossary, Guidance for Industry, Safety testing of drug metabolites, FDA, 2008 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079266.pdf 

drug interactions: Molecular Medicine

drug metabolites: Guidance for Industry, Safety testing of drug metabolites, FDA, 2008 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079266.pdf 

drug safety: "No matter how good the science is," [Sanket] Agrawal [of Relsys]  says, "when a drug is released we can see only a percentage of the risks. If we want to know everything, it means we would never release a drug." The message should be that "all drugs are chemicals and come with side effects, known and unknown. Pharmaceutical companies need to communicate the benefits [correlated to price] versus the risks...and let people make informed decisions."  New Directions in Drug Safety, BioIT World, eCliniqua, Feb 2007    http://www.bio-itworld.com/archive/eclinica/index_02262007.htm 
FDA Drug Safety & Availability http://www.fda.gov/Drugs/DrugSafety/default.htm 

Improving products’ effective clinical safety will increase the industry’s fundamental value proposition to patients, healthcare providers, payors and regulators. The program will focus on pharmacovigilance program implementation and specific strategies and approaches to creating true value from a peri- and post-approval drug safety program. Drug safety programs and monitoring and the approach of this conference are not to look at safety in the silos of early-phase safety or post-approval safety but to view safety holistically, across the lifecycle, especially at the transition from approval to broader use in the marketplace.  Narrower terms: pharmacovigilance, Phase IV, post approval drug safety, preclinical drug safety

Drug Safety Executive Council:  A peer-to-peer membership of over 1,600 drug safety leaders with the common objective of advancing the development of better and safer medicines. http://www.drugsafetycouncil.org/  

Drug Safety Initiative FDA http://www.fda.gov/cder/drugSafety.htm  

EMA: European Medicines Agency http://www.ema.europa.eu/ema/  Was EMEA.

ecotoxicogenomics: Understanding the biological effects of exposures to chemicals in the environment relies on classical methods and emerging technologies in the areas of genomics, proteomics, and metabonomics. Linkages between the historical and newer toxicological tools are currently being developed in order to predict and assess risk. Being able to classify chemicals and other stressors based on effects they have at the molecular, tissue, and organismal levels helps define a systems biology approach to development of streamlined, cost-effective, and comprehensive testing approaches for evaluating environmental hazards. AL Miracle, GT Ankley, Ecotoxicogenomics: linkages between exposure and effects in assessing risks of aquatic contaminants to fish. Reprod Toxicol 19(3): 321- 326, Jan- Feb 2005 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15686867&query_hl=23

ecotoxicology:  To facilitate the application of chemistry in ecotoxicology, there is a need for a glossary addressing the terms in ecotoxicology essential for communication between the disciplines. This project will create such a glossary, reflecting IUPAC's concern about the impact of chemicals on health and the environment. It will also complement the previous projects which resulted in glossaries in toxicology and toxicokinetics. IUPAC, Glossary of terms used in ecotoxicology http://www.iupac.org/projects/2005/2005-047-1-700.html 
Wikipedia http://en.wikipedia.org/wiki/Ecotoxicology  

ED 50:  Abbreviation for median effective dose. 

evidence- based toxicology: Evidence-based toxicology: a comprehensive framework for causation, Guzelian PS, Victoroff MS, Halmes NC, James RC, Guzelian CP., Hum Exp Toxicol. 2005 Apr;24(4): 161-201 

FDA: Every day the Food and Drug Administration (FDA) works to balance expeditious access to drugs with concerns for safety, consonant with its mission to protect and advance the public health. The task is all the more complex given the vast diversity of patients and how they respond to drugs, the conditions being treated, and the range of pharmaceutical products and supplements patients use. Reviewers in the Center for Drug Evaluation and Research (CDER) at the FDA must weigh the information available about a drug’s risk and benefit, make decisions in the context of scientific uncertainty, and integrate emerging information bearing on a drug’s risk-benefit profile throughout the lifecycle of a drug, from drug discovery to the end of its useful life. These processes may have life-or-death consequences for individual patients, and for drugs that are widely used, they may also affect entire segments of the population.  Future of Drug Safety: Promoting and Protecting the Health of the Public, National Academies Press, 2007 http://books.nap.edu/openbook.php?record_id=11750&page=1 

Functional Screens for Drug Safety Testing  May 21-22, 2014 • Boston, MA Program | Register | Download Brochure

good pharmacovigilance practice: 
Good pharmacovigilance practice is generally based on acquiring complete data from spontaneous adverse event reports. http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126834.pdf 

hepatotoxicity
Tackling Drug-Induced and Idiosyncratic Hepatotoxicity June 6-7, 2012 • Philadelphia, PA Order CD    

New Assays and Tools for Predicting Hepatotoxicity June 8-9, 2011 • Philadelphia, PA Order CD  

Mechanistic Insights into Hepatotoxicity July 16, 2010 Order CD 

Wikipedia http://en.wikipedia.org/wiki/Hepatotoxicity   

idiosyncratic toxicity: The primary role of Phase IV post marketing surveillance is to detect rare or idiosyncratic adverse events that do not manifest in the population sizes common to clinical trials ... While clinical forecasting is aimed at predicting safety and efficacy early in the drug development process, rare or idiosyncratic toxicities can only be detected in Phase IV.  There, Phase IV serves as a very important safety net, to catch problems that could not be predicted.  Insight Pharma Reports, Bayesian Forecasting of Phase III Outcomes: The Next Wave in Predictive Tools, June 2007   

Few drug development surprises can be as devastating as toxicity problems that only show up under a combination of conditions as idiosyncratic toxicity. Because of the role of variations in human drug metabolizing enzymes there may only be subtle (or no) evidence of such problems during pre-clinical safety studies. Such problems are also unlikely to show up in all but the largest clinical trials, but if the side effects are serious, it can result in product withdrawal.   

immunogenicity: Assessment of immunogenicity for many types of biotherapeutic continues to challenge the industry. Investigators need to know how to develop and validate assays, when to perform them, and how to interpret the results as a meaningful risk assessment before moving into the clinic. The FDA requirement for neutralizing antibody assays is a particular hurdle. In the clinic, investigators need to work out how to deal with interfering drug and to understand the significance of pre-existing antibodies. Immunogenicity for Regulatory SuccessImmunogenicity for Regulatory Success May 7-8, 2014 • PEGS Boston, MA Program | Register | 

Immunogenicity Prediction and Mitigation  May 8-9, 2014 • PEGS Boston, MA Program | Register | 
Immunogenicity Prediction and Mitigation

Immunogenicity & PKPD SummitImmunogenicity & PKPD Summit November 11-13, 2013 • Washington, DC Program | Register | Download Brochure
Immunogenicity Assessment and Strategies November 11-12, 2013 • Washington, DC Program | Register | Download Brochure
Immunogenicity Risk Assessment and Mitigation  November 12-13, 2013  Washington, DC Program | Register | Download Brochure

immunoinformatics: the application of informatics techniques to molecules of the immune system. One of the key goals of immunoinformatics is the development of computer aided vaccine design (CAVD), or computational vaccinology, and its application to the search for new vaccines. Key to solving this challenge is the prediction of immunogenicity, be that at the level of epitope, subunit vaccine or attenuated pathogen. Flower DR, Doytchinova IA Immunoinformatics and the prediction of immunogenicity Appl Bioinformatics. 2002;1(4):167-176  http://www.ncbi.nlm.nih.gov/pubmed/15130835 .

immunotoxicology:
Immunotoxicology of both organic and inorganic substances is presently of great interest in occupational and environmental health  ... In preparing the immunochemical papers, it became clear that there is a large number of specialized terminology foreign to chemists and not included in the Glossary of Terms Used in Toxicology (2nd ed.). In addition, a number of terms are somewhat ambiguous even within the discipline of immunology, and their precise definition will help to clarify regulatory and legislative discussion. We believe that this will add significantly to the value of the Immunosensitization project, as well as being an essential addition to the toxicology glossaries referred to above.  IUPAC Glossary of terms used in immunotoxicology project, 2008   http://www.iupac.org/web/ins/2007-053-1-700 

in vitro adventitious assay: Assays & screening

LD 50:  The dose of a substance that will kill half (50%) of the treated test animals when given as a single dose.  A measure of acute toxicity. Chemical Hygiene Glossary of Terms, Environment, Health & Safety Lab, Lawrence Berkeley National Laboratory, US

metabolite: A compound derived from the parent drug through Phase I and/or Phase II metabolic pathways, Glossary,  Guidance for Industry, Safety testing of drug metabolites, FDA, 2008 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079266.pdf 

Any intermediate or product resulting from metabolism. IUPAC  International Union of Pure and Applied Chemistry, Glossary for Chemists of terms used in biotechnology. Recommendations, Pure & Applied Chemistry 64 (1): 143-168, 1992  See also Metabolic Profiling

mitochondrial toxicity: Targeting Mitochondrial Dysfunction & ToxicityTargeting Mitochondrial Dysfunction & Toxicity  March 19-20, 2014 • Boston, MA Program | Register | Download Brochure

molecular toxicology:  The scope [of the Journal of Biochemical and Molecular Toxicology] includes effects on the organism at all stages of development, on organ systems, tissues, and cells as well as on enzymes, receptors, hormones, and genes. The biochemical and molecular aspects of uptake, transport, storage, excretion, activation and detoxication of drugs, agricultural, industrial and environmental chemicals, natural products and food additives are all subjects suitable for publication. Of particular interest are aspects of molecular biology related to biochemical toxicology. These include studies of the expression of genes related to detoxication and activation enzymes, toxicants with modes of action involving effects on nucleic acids, gene expression and protein synthesis, and the toxicity of products derived from biotechnology. Journal of Biochemical and Molecular Toxicology, Wiley Periodicals http://www3.interscience.wiley.com/cgi-bin/jabout/38998/ProductInformation.html

nanotoxicology: Nanotoxicology invites contributions addressing research relating to the potential for human and environmental exposure, hazard and risk associated with the use and development of nano-structured materials. In this context, the term nano-structured materials has a broad definition, including ‘materials with at least one dimension in the nanometer size range’. These nanomaterials range from nanoparticles and nanomedicines, to nano-surfaces of larger materials and composite materials. The range of nanomaterials in use and under development is extremely diverse, so this journal includes a range of materials generated for purposeful delivery into the body (food, medicines, diagnostics and prosthetics), to consumer products (e.g. paints, cosmetics, electronics and clothing), and particles designed for environmental applications (e.g. remediation). It is the nano-size range if these materials which unifies them and defines the scope of Nanotoxicology.  While the term ‘toxicology’ indicates risk, the journal Nanotoxicology also aims to encompass studies that enhance safety during the production, use and disposal of nanomaterials. Well-controlled studies demonstrating a lack of exposure, hazard or risk associated with nanomaterials, or studies aiming to improve biocompatibility are welcomed and encouraged, as such studies will lead to an advancement of nanotechnology. Furthermore, many nanoparticles are developed with the intention to improve human health (e.g. antimicrobial agents), and again, such articles are encouraged. In order to promote quality. Aims and Scope, Nanotoxicology, Informa http://informahealthcare.com/page/nan/Description

Wikipedia http://en.wikipedia.org/wiki/Nanotoxicology 

nephrotoxicity
:
Detecting Nephrotoxicity Using Early Markers and Imaging Tools June 7-8, 2011 • Philadelphia, PA Order CD

New Tools for Detecting Nephrotoxicity June 15-16, 2010 • Philadelphia, PA  Order CD  

pharmacoepidemiology: may be defined as the study of the utilization and effects of drugs in large numbers of people. To accomplish this study, pharmacoepidemiology borrows from both pharmacology and epidemiology. Thus, pharmacoepidemiology can be called a bridge science spanning both pharmacology and epidemiology. Pharmacology is the study of the effect of drugs and clinical pharmacology is the study of effect of drugs in humans. Part of the task of clinical pharmacology is to provide a risk benefit assessment for the effect of drugs in patients. Doing the studies needed to provide an estimate of the probability of beneficial effects in populations, or the probability of adverse effects in populations and other parameters relating to drug use may benefit from using epidemiological methodology. Pharmacoepidemiology then can also be defined as the application of epidemiological methods to pharmacological issues. ISPE International Society for PharmacoEpidemiology 2011  http://www.pharmacoepi.org/about/index.cfm 

pharmacological biomarkers: Biomarkers

pharmacologically active metabolite: A metabolite that has pharmacological activity at the target receptor. The activity may be greater than, equal to, or less than that of the patent drug. Glossary,  Guidance for Industry, Safety testing of drug metabolites, FDA, 2008 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079266.pdf 

pharmacovigilance:  is defined as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems. The Importance of Pharmacovigilance, WHO 2011 http://www.who.int/medicines/areas/quality_safety/safety_efficacy/pharmvigi/en/index.html 

The process of (a) monitoring medicines as used in everyday practice to identify previously unrecognised or changes in the patterns of their adverse effects; (b) assessing the risks and benefits of medicines in order to determine what action, if any, is necessary to improve their safe use; (c) providing information to users to optimise safe and effective use of medicines; (d) monitoring the impact of any action taken.  Medicines Control Agency, UK, Pilot publication scheme, Glossary of terms, 2003 http://www.mca.gov.uk/pilot/app1.htm#A

Good Pharmacovigilance Practices, FDA 2005 http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126834.pdf 
Wikipedia http://en.wikipedia.org/wiki/Pharmacovigilance   Related term: post marketing surveillance  Broader term: drug safety

Phase IV/ postmarketing surveillance: At this stage, after a drug has been launched, pharmaceutical companies may conduct further studies of its performance, often examining long- term safety.  See also clinical trials, phase I, II, III  post approval drug safety:     
Broader term: drug safety  Related term: pharmacovigilance

post marketing surveillance: Managing Post-Marketing Studies and RegistriesManaging Post-Marketing Studies and Registries  February 4-5, 2014 • SCOPE  Miami, FL Program | Register | Download Brochure

See  also Phase IV Post Marketing Surveillance 

predictive ADME:
The completion of the Human Genome Project and recent advances in our understanding of the molecular mechanisms of diseases have provided increasing numbers of newly defined biological pathways and networks with potential preventive or therapeutic targets. The development of molecular diversity libraries and screening of these libraries have provided tremendous opportunities to discover new chemical and biological agents for the prevention and treatment of diseases. This created the belief that increasing numbers of new molecular entities would enter clinical testing and would receive approval from the Food and Drug Administration (FDA) to treat human disorders. However, this has not occurred. Many candidate agents are failing during clinical testing because of their unfavorable pharmacokinetic properties, unacceptable adverse effects, or major toxicities, as well as the lack of efficacy.

The safety of each new chemical entity must be demonstrated prior to its entry into clinical trials. Investigational New Drug (IND) applications to the FDA require chemistry, manufacturing, and control information and results from preclinical toxicology studies for the safety of new agents. Results of nonclinical pharmacokinetic studies for defining ADME properties, addressing important safety issues, or assisting the evaluation of toxicology data for investigational new agents are highly desirable in IND submissions. Novel preclinical tools for Predictive ADME-Toxicology RFA Number: RFA-RM-04-023, 2004   http://grants.nih.gov/grants/guide/rfa-files/RFA-RM-04-023.html#PartI 

predictive safety: Unexpected toxicity is the single greatest cause of pipeline attrition. Despite the fact that a typical preclinical safety program will consume about 1,300 rats and 90 dogs, there is no guarantee that the compound will not present safety problems serious enough to warrant termination. Insight Pharma Report  Outlook for Predictive Safety Technologies, 2006

Predictive Safety Testing Consortium: http://www.fda.gov/oc/initiatives/criticalpath/projectsummary/consortium.html  See also Biomarkers

predictive toxicogenomics: A number of novel approaches to toxicology research that have become available over the past five years that are raising optimism for dramatic improvements in the field. Strategic regulatory, and marketplace issues are driving growth of toxicogenomic and predictive toxicology applications. The ability to predict the toxic effects of potential new drugs is crucial to prioritizing compound pipelines and eliminating costly failures in drug development. The inability to accurately predict toxicity early in drug development cost the pharmaceutical industry $8 billion in 2003, approximately one-third the cost of all drug failures. Even when drugs successfully obtain FDA approval and reach the market, they remain vulnerable to costly safety issues.  

predictive toxicology: An in-depth survey of strategies to characterize chemical structures and biological systems-covering prediction methods and algorithms, sources of high-quality toxicity data, the most important commercial and noncommercial predictive toxicology programs, and advanced technologies in computational chemistry and biology, statistics, and data mining. Predictive Toxicology The Book, CRC Press, 2005 http://www.predictive-toxicology.org/ 

protein aggregation: Protein Aggregation and Emerging Analytical Tools January 16-17, 2014 • PepTalk Palm Springs, CA Program | Register | Download Brochure

PSURs Periodic Safety Update Report: Designed to be a stand- alone document that allows a periodic but comprehensive assessment of the worldwide safety data of a marketed drug or biological product. MJ Klepper, The periodic safety update report as a pharmacovigilance tool, Drug Safety 27(8): 569- 578, 2004

reactive metabolites: Many drugs withdrawn from the market for toxicity reasons have later been shown to undergo bioactivation to reactive intermediates.  Still, there remain unanswered questions regarding the relationship between reactive metabolites and idiosyncratic toxicity.  For example, although the issue of protein binding has been recognized for decades, the exact mechanisms leading to drug toxicity are still being worked out.  Strategies that medicinal chemists employ in designing drugs with the best safety profile should incorporate our current understanding of structure-toxicity relationships and should also reflect our knowledge about the relationship of dose and risk of idiosyncratic toxicity.  Newer tools such as in silico modeling of drug metabolism can also address bioactivation issues and may be a valuable tool to help design safer drugs.  Reactive Metabolites in Drug Discovery and Development DVD August 18, 2010 •

REMS Risk Evaluation and Mitigation Strategy : The Food and Drug Administration Amendments Act of 2007 gave FDA the authority to require a Risk Evaluation and Mitigation Strategy (REMS) from manufacturers to ensure that the benefits of a drug or biological product outweigh its risks.  Approved Risk Evaluation and Mitigation Strategies , 2010 http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm

safety pharmacology: Pharmacology studies can be divided into three categories: primary pharmacodynamic, secondary pharmacodynamic, and safety pharmacology studies. For the purpose of this document, safety pharmacology studies are defined as those studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure in the therapeutic range and above. ICH Guidance for Industry, S7A Safety Pharmacology Studies for Human Pharmaceuticals,  2001 http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm129156.pdf 

A distinct scientific discipline that integrates the best practices of pharmacology, physiology and toxicology. The objective of Safety Pharmacology studies is to further the discovery, development and safe use of biologically active chemical entities by the identification, monitoring and characterization of potentially undesirable pharmacodynamic activities in nonclinical studies.  Mission Statement, Safety Pharmacology Society http://www.safetypharmacology.org/mission.asp 

Sentinel Initiative: On May 22, 2008, FDA launched the Sentinel Initiative with the ultimate goal of creating and implementing the Sentinel System--a national, integrated, electronic system for monitoring medical product safety. The Sentinel System will enable FDA to query multiple, existing data sources, such as electronic health record systems and medical claims databases, for information about medical products. The system will enable FDA to query data sources at remote locations, consistent with strong privacy and security safeguards.  Data sources will continue to be maintained by their owners.  This historic new system will strengthen FDA's ability to monitor the performance of a product throughout its entire life cycle. FDA, US http://www.fda.gov/oc/initiatives/advance/sentinel/ 

side- effect: The old term "side effect" has been used in various ways in the past, usually to describe negative (unfavourable) effects, but also positive (favourable) effects. It is recommended that this term no longer be used and particularly should not be regarded as synonymous with adverse event or adverse reaction. ICH Topic E 2 A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, EMEA European Agency for the Evaluation of Medicinal Products CPMP/ICH/377/95, 1994 ; Related terms: ADE adverse drug effect, ADR adverse drug reaction

Stem Cells in Toxicity Testing DVD November 4, 2010 •

susceptibility: This large diversity in responsiveness among individuals to environmental toxicants makes it difficult to determine actual risks, particularly at the low doses to which most people are exposed. Opportunities now exist for studies of genetic susceptibility for cancer and other diseases in which an environmental component can be presumed. Knowledge from such studies could, in the future, allow markers of genetic susceptibility to be incorporated into epidemiologic studies. This, in turn, would permit adjustment of  interpretation of results to account for genetic susceptibility, thus greatly enhancing the sensitivity and power of these studies to detect environmental components of important diseases. Other projects being considered are a nutrition initiative to determine how nutritional status alters disease susceptibility, and development of transgenic mice that carry important environmental response gene. NIEHS Strategic Plan 2000 "Individual susceptibility", National Institute of Environmental Health Sciences, US, March 2000 http://www.niehs.nih.gov/external/plan2000/suscptblty.htm

Susceptibility seems essentially synonymous with predisposition. Are there differences? Related terms: toxicogenomics, Molecular diagnostics & genetic testing genetic screening, predisposition test, predictive test, risk communication

systems pharmacology: Pharmacogenomics

systems toxicology: the combination of traditional toxicology methods with new strategies and tools for integrating high-throughput transcriptomics, proteomics, and metabolomics data. The goal is to better understand and predict potential toxicities at an early stage of drug development, so that biopharmas can gain deeper insights into the biology underlying toxicity, and make “go/ no-go” decisions well before committing to further development and clinical trials.  Kurt Zingler, Cross-Omics and Systems Toxicology, BioIT World 6 (9):  25,  Nov 2007  http://www.bio-itworld.com/issues/2007/nov/cross-omics-and-systems-toxicology/  

BEH.201 deals with the chemical and biological analysis of the metabolism and distribution of drugs, toxins and chemicals in animals and humans. The subject focuses on the mechanisms by which drugs and toxins cause therapeutic and toxic responses, as well as the use of metabolism and toxicity as a basis for drug development. MIT Graduate Studies in Applied Biosciences, Biological Engineering Fall 2003  http://stellar.mit.edu/S/course/BE/fa03/be.201/index.html   Related terms: -Omes & -omics  cross-omics

therapeutic index TI:  The ratio of the LD50 to the effective dose (ED50). How close is the dose which will kill 50% of the tested animals to the dose required for the desired effect in humans? If these two doses are very close to each other, then there is an obvious danger in using the drug with humans. [US Dept. of Justice in the matter of MDMA Scheduling, Docket No. 84- 48, 1986 www.streetdrugs.org] http://www.mninter.net/~publish/mdma.htm  Related terms: ED 50, LD 50 Lethal Dose 50.

toxicity testing: An important part of the drug- lead- optimization process in which investigational compounds are tested for their potential to cause side effects. CHA, Cambridge Healthtech Advisors Model Animal Systems: Emerging Applications and Commercial Opportunities in Drug Discovery and Development, report, 2004  

Both animal models and cellular assays are utilized. 

toxicity tests: An array of tests used to determine the toxicity of a substance to living systems. These include tests on clinical drugs, foods, and environmental pollutants. MeSH 1995

toxicogenomics: An approach to toxicology measuring how people's genomes respond to environmental stressors or toxicants.  Combines genome- wide gene expression profiling with protein expression patterns using bioinformatics to understand the role of gene- environment interactions in disease, understand how chemicals affect the expression of genes, characterize normal genetic and metabolic pathways, and learn how disease occurs when these pathways malfunction. Cambridge Healthtech Advisors, Clinical Genomics: The Impact of Genomics on Clinical Trials and Medical Practice report, 2004

The study of the structure and output of the genome as it responds to adverse xenobiotic exposure. Ulrich RG. The toxicogenomics of nuclear receptor agonists. Current Opinion in Chemical Biology 7(4) 505- 510, August 2003

The ability to predict the toxic effects of potential new drugs is crucial to prioritizing compound pipelines and eliminating costly failures in drug development. Toxicogenomics, which deals primarily with the effects of compounds on gene expression patterns in target cells or tissues, is emerging as a key approach in screening new drug candidates because it may reveal genetic signatures that can be used to predict toxicity in these compounds. Insight Pharma Reports Toxicogenomics: The Promise of Safer, Smarter Drug Development, 2005

toxicoinformatics: An emerging scientific discipline that integrates approaches from multidisciplinary fields of bioinformatics, chemoinformatics, computational toxicology, informatics technologies and physiologically- based pharmacokinetic modeling with the objective of knowledge discovery and the elucidation of mechanisms of toxicity. NCTR's Center for Toxicoinformatics, National Center for Toxicological Research, FDA, 2003  http://www.fda.gov/nctr/science/centers/toxicoinformatics/  

toxicokinetics: Process of the uptake of potentially toxic substances by the body, the biotransformation they undergo, the distribution of the substances and their metabolites in the tissues, and the elimination of the substances and their metabolites from the body. Both the amounts and the concentrations of the substances are studied. The term has essentially the same meaning as pharmacokinetics, but the latter term should be restricted to the study of pharmaceutical substances. IUPAC Compendium 
Wikipedia http://en.wikipedia.org/wiki/Toxicokinetics  See also under pharmacokinetics: Pharmacogenomics

toxicology: Can be described, according to a U.S. National Library of Medicine online tutorial, as "the study of the adverse effects of chemicals or physical agents on living organisms." Such effects run the gamut from immediate death to subtle effects that manifest only months or years after exposure. Toxic substances may affect various levels of the body, such as a particular organ, cell type, or biomolecule.  Narrower terms: biochemical toxicology, molecular toxicology, nanotoxicology 

toxicoproteomics: The emerging field of toxicoproteomics has been boosted by quantitative and qualitative proteomic technologies and its increasing applications in toxicology research. The discipline is focused on the proteomic studies of toxicity, caused in response to toxic chemicals and environmental exposures, both in episodes of acute exposure to toxicants along with the long-term development of disease. Toxicoproteomics uses the discovery potential of proteomics in toxicology research by applying global protein measurement technologies to biofluids and tissues after host exposure to injurious agents. This field is challenging too, largely due to the shear size of the proteome and the massive data that are generated by it. Toxicol Mech Methods. 2010 Sep;20(7):415-23. doi: 10.3109/15376511003667842.Toxicoproteomics: new paradigms in toxicology research. George JSingh RMahmood ZShukla Y.  http://www.ncbi.nlm.nih.gov/pubmed/20175663

Toxicoproteomics is the use of global protein expression technologies to better understand environmental and genetic factors, both in episodes of acute exposure to toxicants and in the long-term development of disease. Integrating transcript, protein, and toxicology data is a major objective of the field of toxicogenomics. KB Tomer, DB Merrick, Toxicoproteomics: a parallel approach to identifying biomarkers Environmental Health Perspectives 2003 Aug;111(11): A578- 579. 

transcriptomics:
In the context of toxicology studies, involves assessing changes in transcription initiation, processing, and degradation after chemical exposure using glass and membrane DNA microarrays and low- output tools, such as ribonuclease protection assays and real-time PCR.

uncertainty: Molecular Medicine

xenobiotic: A compound foreign to an organism. From the Greek xenox = foreign, bios = life. [IUPAC Medicinal Chemistry] Principal xenobiotics include drugs, carcinogens and various compounds that have been introduced into the environment by artificial means. IUPAC Bioinorganic

A key term in toxicology (means foreign substance) is used to identify clearly toxic substances, such as lead, or beneficial therapeutic agents, many of which become toxic at elevated dosage levels.  Drugs can generally be characterized as having a nontoxic or beneficial dose, a toxic dose, and a lethal dose. For example, two 650 mg aspirin tablets are usually beneficial, while seven tablets are usually toxic, and 60 tablets can be lethal. Similarly, a blood alcohol level of 0.05% is generally nontoxic, while 0.10% is toxic, and 0.50% can be lethal. However, it is important to note that such levels are averages, and individuals can manifest significant departures from the mean, depending on expression levels of key metabolic enzymes and the presence of polymorphisms that degrade or enhance the activity of these enzymes.

Bibliography
ATSDR Glossary, Agency for Toxic Substances & Disease Registry, http://www.atsdr.cdc.gov/glossary.html 2009
Glossary of IRIS [Integrated Risk Information System] Terms, Environmental Protection Agency, 2009, 100+ terms http://www.epa.gov/ncea/iris/help_gloss.htm 

IPCS International Program on Chemical Safety/ISEA International Society for Exposure Analysis Glossary http://www.nature.com/jes/journal/v15/n1/full/7500411a.html  37 terms

IUPAC, Abbreviations and acronyms of names of International Bodies, IUPAC Glossary of Toxicology, 2007 http://sis.nlm.nih.gov/enviro/iupacglossary/annex2.html 
IUPAC, Explanatory dictionary of key terms used in toxicology, 2007 http://www.iupac.org/publications/pac/79/9/1583/ 
IUPAC International Union of Pure and Applied Chemistry, CHEMISTRY AND HUMAN HEALTH DIVISION, IUPAC GLOSSARY OF TERMS USED IN TOXICOLOGY, 2nd EDITION - IUPAC RECOMMENDATIONS 2007 Published in Pure Appl. Chem., Vol. 79, No. 7, pp. 1153-1344, 2007 http://sis.nlm.nih.gov/enviro/iupacglossary/frontmatter.html
IUPAC  International Union of Pure and Applied Chemistry, Glossary of Terms used in Bioinorganic Chemistry, Recommendations, 1997. 450+ definitions. http://www.chem.qmw.ac.uk/iupac/bioinorg/
IUPAC, Glossary of terms used in toxicology, 2007 http://sis.nlm.nih.gov/enviro/iupacglossary/frontmatter.html  
IUPAC, Glossary for toxicokinetics of chemicals, 365 terms. http://www.iupac.org/publications/pac/2004/pdf/7605x1033.pdf  Published Pure & Applied Chemistry 76 (5): 1033-1082, 2004
WHO, Adverse Reaction Terminology, 2009 http://www.umc-products.com/graphics/3036.pdf 

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