β2-adrenoceptor agonists and antagonists and risk of Parkinson's disease.

Background: β2-adrenoreceptors have recently been identified as regulators of the α-synuclein gene, which is implicated in the pathogenesis of Parkinson's disease.

Objective: The objectives of this study were to assess the association between use of β2-agonists and β-antagonists and the risk of developing PD.

Methods: We conducted a nested case-control study in a cohort of 1,762,164 adults without a diagnosis of PD.

Drug Burden Index and Its Association With Hip Fracture Among Older Adults: A National Population-Based Study.

Background: The Drug Burden Index (DBI) calculates the total sedative and anticholinergic load of prescribed medications and is associated with functional decline and hip fractures in older adults. However, it is unknown if confounding factors influence the relationship between the DBI and hip fractures. The objective of this study was to evaluate the association between the DBI and hip fractures, after correcting for mortality and multiple potential confounding factors.

Drug Burden and its Association with Falls Among Older Adults in New Zealand: A National Population Cross-Sectional Study.

Background: Adverse outcomes associated with advanced diseases are often exacerbated by polypharmacy.

Objectives: The current study investigated an association between exposure to anticholinergic and sedative medicines and falls in community-dwelling older people, after controlling for potential confounders.

Methods: We conducted a retrospective cross-sectional study of a continuously recruited national cohort of community-dwelling New Zealanders aged 65 years and over.

Use of Biomedical Ontologies for Integration of Biological Knowledge for Learning and Prediction of Adverse Drug Reactions.

Drug-induced toxicity is a major public health concern that leads to patient morbidity and mortality. To address this problem, the Food and Drug Administration is working on the PredicTox initiative, a pilot research program on tyrosine kinase inhibitors, to build mechanistic and predictive models for drug-induced toxicity. This program involves integrating data acquired during preclinical studies and clinical trials within pharmaceutical company development programs that they have agreed to put in the public domain and in publicly available biological, pharmacological, and chemical databases.

In Vitro-In Vivo Extrapolation of Metabolism- and Transporter-Mediated Drug-Drug Interactions-Overview of Basic Prediction Methods.

Evaluation of drug-drug interaction (DDI) risk is vital to establish benefit-risk profiles of investigational new drugs during drug development. In vitro experiments are routinely conducted as an important first step to assess metabolism- and transporter-mediated DDI potential of investigational new drugs. Results from these experiments are interpreted, often with the aid of in vitro-in vivo extrapolation methods, to determine whether and how DDI should be evaluated clinically to provide the basis for proper DDI management strategies, including dosing recommendations, alternative therapies, or contraindications under various DDI scenarios and in different patient population.

Linking MedDRA(®)-Coded Clinical Phenotypes to Biological Mechanisms by the Ontology of Adverse Events: A Pilot Study on Tyrosine Kinase Inhibitors.

Introduction: A translational bioinformatics challenge exists in connecting population and individual clinical phenotypes in various formats to biological mechanisms. The Medical Dictionary for Regulatory Activities (MedDRA(®)) is the default dictionary for adverse event (AE) reporting in the US Food and Drug Administration Adverse Event Reporting System (FAERS). The ontology of adverse events (OAE) represents AEs as pathological processes occurring after drug exposures.

Bidirectional interactions between indomethacin and the murine intestinal microbiota.

The vertebrate gut microbiota have been implicated in the metabolism of xenobiotic compounds, motivating studies of microbe-driven metabolism of clinically important drugs. Here, we studied interactions between the microbiota and indomethacin, a nonsteroidal anti-inflammatory drug (NSAID) that inhibits cyclooxygenases (COX) -1 and -2. Indomethacin was tested in both acute and chronic exposure models in mice at clinically relevant doses, which suppressed production of COX-1- and COX-2-derived prostaglandins and caused small intestinal (SI) damage.

Replication - why we need to publish our findings.

The pharmacology research sector is changing to accommodate a need for greater transparency and better standards. The themed articles contained herein explain how Pharmacology Research and Perspectives (PR&P) has responded to this agenda. This issue of PR&P contains three articles that consider the reliability of pharmacological research publications, and approaches to their improvement in this regard.

Logic-Based and Cellular Pharmacodynamic Modeling of Bortezomib Responses in U266 Human Myeloma Cells.

Systems models of biological networks show promise for informing drug target selection/qualification, identifying lead compounds and factors regulating disease progression, rationalizing combinatorial regimens, and explaining sources of intersubject variability and adverse drug reactions. However, most models of biological systems are qualitative and are not easily coupled with dynamical models of drug exposure-response relationships. In this proof-of-concept study, logic-based modeling of signal transduction pathways in U266 multiple myeloma (MM) cells is used to guide the development of a simple dynamical model linking bortezomib exposure to cellular outcomes.

Hypothyroidism is a Risk Factor for New-Onset Diabetes: A Cohort Study.

Objective: To identify risk factors for the development of statin-associated diabetes mellitus (DM).

Research Design And Methods: The study was conducted in two phases. Phase one involved high-throughput in silico processing of a large amount of biomedical data to identify risk factors for the development of statin-associated DM.

Adverse Event Detection and Labeling in Pediatric Drug Development: Antiretroviral Drugs.

Background: Pediatric safety studies are conducted for drugs undergoing development for use in pediatric patients. The objective of this study was to describe safety studies and compare adverse events of antiretroviral drugs between pediatric patients and adult subjects.

Methods: Pediatric and adult adverse event data were obtained from US Food and Drug Administration (FDA)-approved drug labels for 9 antiretroviral drugs with pediatric indications approved by the FDA prior to 2013.

Revision of instructions to authors for pharmacology research and perspectives: enhancing the quality and transparency of published work.

e00106

Advice on statistical analysis, and new journal guidance for experimental design and analysis.

e00095

Consensus recommendations for systematic evaluation of drug-drug interaction evidence for clinical decision support.

Background: Healthcare organizations, compendia, and drug knowledgebase vendors use varying methods to evaluate and synthesize evidence on drug-drug interactions (DDIs). This situation has a negative effect on electronic prescribing and medication information systems that warn clinicians of potentially harmful medication combinations.

Objective: The aim of this study was to provide recommendations for systematic evaluation of evidence for DDIs from the scientific literature, drug product labeling, and regulatory documents.

The utility of modeling and simulation in drug development and regulatory review.

US Food and Drug Administration (FDA) has identified innovation in clinical evaluations as a major scientific priority area. This paper provides case studies and updates to describe the efforts by the FDA's Office of Clinical Pharmacology in its development and application of regulatory science, focusing on modeling and simulation. Key issues and challenges are identified that need to be addressed to promote the uptake of modeling and simulation approaches in drug regulation.

A 2012 Workshop: Vaccine and Drug Ontology in the Study of Mechanism and Effect (VDOSME 2012).

Vaccines and drugs have contributed to dramatic improvements in public health worldwide. Over the last decade, there have been efforts in developing biomedical ontologies that represent various areas associated with vaccines and drugs. These ontologies combined with existing health and clinical terminology systems (e.

Systems pharmacology to predict drug toxicity: integration across levels of biological organization.

To achieve sensitive and specific mechanism-based prediction of drug toxicity, the tools of systems pharmacology will be integrated using structured ontological approaches, analytics, mathematics, and statistics. Success of this effort is based on the assumption that a systems network that consists of drug-induced perturbations of physiological functions can be characterized. This network spans the hierarchy of biological organization, from gene to mRNA to protein to intracellular organelle to cell to organ to organism.

Evaluation of exposure change of nonrenally eliminated drugs in patients with chronic kidney disease using physiologically based pharmacokinetic modeling and simulation.

Chronic kidney disease, or renal impairment (RI) can increase plasma levels for drugs that are primarily renally cleared and for some drugs whose renal elimination is not a major pathway. We constructed physiologically based pharmacokinetic (PBPK) models for 3 nonrenally eliminated drugs (sildenafil, repaglinide, and telithromycin). These models integrate drug-dependent parameters derived from in vitro, in silico, and in vivo data, and system-dependent parameters that are independent of the test drugs.

Pharmacoepidemiology in the postmarketing assessment of the safety and efficacy of drugs in older adults.

Much of the information on safety and efficacy of drugs in older people is obtained after marketing. Pharmacoepidemiologic studies play an increasing role in obtaining this information. Pharmacoepidemiologic studies contribute significantly to knowledge of risks associated with medicines in older people and less so to that of benefits.

Geriatric drug evaluation: where are we now and where should we be in the future?

The older population is currently the fastest growing age group in the United States, and this trend is expected to continue for several decades. Older individuals, in general, have a higher disease burden compared with younger adults and are the major users of medications, yet premarketing drug clinical trials have often excluded them even for the drugs that have high utility in this age group. Extrapolation of clinical results from younger to older individuals does not provide adequate benefit-risk estimation, and the frequent need for dose adjustment in older patients from initially approved doses exemplifies the current lack of adequate clinical data in the elderly.