Abstract:
:Systems approaches have long been used in pharmacology to understand drug action at the organ and organismal levels. The application of computational and experimental systems biology approaches to pharmacology allows us to expand the definition of systems pharmacology to include network analyses at multiple scales of biological organization and to explain both therapeutic and adverse effects of drugs. Systems pharmacology analyses rely on experimental "omics" technologies that are capable of measuring changes in large numbers of variables, often at a genome-wide level, to build networks for analyzing drug action. A major use of omics technologies is to relate the genomic status of an individual to the therapeutic efficacy of a drug of interest. Combining pathway and network analyses, pharmacokinetic and pharmacodynamic models, and a knowledge of polymorphisms in the genome will enable the development of predictive models of therapeutic efficacy. Network analyses based on publicly available databases such as the U.S. Food and Drug Administration's Adverse Event Reporting System allow us to develop an initial understanding of the context within which molecular-level drug-target interactions can lead to distal effectors in a process that results in adverse phenotypes at the organ and organismal levels. The current state of systems pharmacology allows us to formulate a set of questions that could drive future research in the field. The long-term goal of such research is to develop polypharmacology for complex diseases and predict therapeutic efficacy and adverse event risk for individuals prior to commencement of therapy.
journal_name
Annu Rev Pharmacol Toxicoljournal_title
Annual review of pharmacology and toxicologyauthors
Zhao S,Iyengar Rdoi
10.1146/annurev-pharmtox-010611-134520subject
Has Abstractpub_date
2012-01-01 00:00:00pages
505-21eissn
0362-1642issn
1545-4304journal_volume
52pub_type
杂志文章,评审abstract::Bisphosphonates (BPs) are pyrophosphate analogs in which the oxygen bridge has been replaced by carbon and diverse carbon side chains have generated a large family of compounds. Several are potent inhibitors of bone destruction (resorption) and are in clinical use for the treatment and prevention of osteoporosis, Page...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章,评审
doi:10.1146/annurev.pharmtox.38.1.375
更新日期:1998-01-01 00:00:00
abstract::In this review, we discuss the potential pharmacological targeting of a set of powerful epigenetic mechanisms: DNA methylation control systems in the central nervous system (CNS). Specifically, we focus on the possible use of these targets for novel future treatments for learning and memory disorders. We first describ...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章,评审
doi:10.1146/annurev-pharmtox-010814-124527
更新日期:2015-01-01 00:00:00
abstract::Determining the potential toxicity of compounds early in the drug discovery process can be extremely beneficial in terms of both time and money conservation. Because of the speed of modern chemical synthesis and screening, to accurately evaluate the large number of compounds being produced, toxicology assays must have...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章,评审
doi:10.1146/annurev.pharmtox.40.1.335
更新日期:2000-01-01 00:00:00
abstract::Oral vaccination enables pain-free and self-administrable vaccine delivery for rapid mass vaccination during pandemic outbreaks. Furthermore, it elicits systemic and mucosal immune responses. This protects against infection at mucosal surfaces, which may further enhance protection and minimize the spread of disease. T...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章
doi:10.1146/annurev-pharmtox-030320-092348
更新日期:2021-01-06 00:00:00
abstract::The theme "New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development" links 13 articles in this volume of the Annual Review of Pharmacology and Toxicology (ARPT). The engaging prefatory articles by Arthur Cho and Robert Lefkowitz set the stage for this theme and for the revie...
journal_title:Annual review of pharmacology and toxicology
pub_type:
doi:10.1146/annurev-pharmtox-092617-121952
更新日期:2018-01-06 00:00:00
abstract::Long-acting contraceptives are the most effective reversible contraceptive methods. Increasing patients' access to these contraceptives may translate into fewer unintended pregnancies and lead to substantial individual and public health benefits. However, development of long-acting products can be complex and challeng...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章
doi:10.1146/annurev-pharmtox-031120-015212
更新日期:2021-01-06 00:00:00
abstract::Nuclear receptors (NR) are ligand-modulated transcription factors that play diverse roles in cell differentiation, development, proliferation, and metabolism and are associated with numerous liver pathologies such as cancer, steatosis, inflammation, fibrosis, cholestasis, and xenobiotic/drug-induced liver injury. The ...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章,评审
doi:10.1146/annurev-pharmtox-010715-103209
更新日期:2016-01-01 00:00:00
abstract::Recent discoveries of novel and potentially important biological activity have spurred interest in the chemistry and biochemistry of nitroxyl (HNO). It has become clear that, among all the nitrogen oxides, HNO is unique in its chemistry and biology. Currently, the intimate chemical details of the biological actions of...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章,评审
doi:10.1146/annurev.pharmtox.45.120403.095959
更新日期:2005-01-01 00:00:00
abstract::Recent advances in cell signaling research suggest that multiple sets of signal transducing molecules are preorganized and sequestered in distinct compartments within the cell. These compartments are assembled and maintained by specific cellular machinery. The molecular ecology within a compartment creates an environm...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章,评审
doi:10.1146/annurev.pharmtox.45.120403.095807
更新日期:2005-01-01 00:00:00
abstract::Major advances in scientific discovery and insights can result from the development and use of new techniques, as exemplified by the work of Solomon Snyder, who writes a prefatory article in this volume. The Editors have chosen "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology" as the Theme ...
journal_title:Annual review of pharmacology and toxicology
pub_type:
doi:10.1146/annurev-pharmtox-091616-023708
更新日期:2017-01-06 00:00:00
abstract::The recent advances made in elucidating the processes of nociception have altered the way that chronic pain therapy and analgesic drug development are approached. Recent studies have highlighted new targets for drug discovery, including inhibition of inflammatory mediators (kinins, growth factors), newly expressed pro...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章,评审
doi:10.1146/annurev.pa.36.040196.001345
更新日期:1996-01-01 00:00:00
abstract::Either an excess or a deficiency of vitamin A and related compounds (retinoids) causes abnormal morphological development (teratogenesis). Potential retinoid sources come from dietary intake, nutritional supplements, and some therapeutic drugs. Therefore, understanding the mechanisms of retinoid teratogenesis is impor...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章,评审
doi:10.1146/annurev.pharmtox.39.1.399
更新日期:1999-01-01 00:00:00
abstract::Arylamines and heterocyclic arylamines (HAAs) are of particular interest because of demonstrated carcinogenicity in animals and humans and the broad exposure to many of these compounds. The activation of these, and also some arylamine drugs, involves N-hydroxylation, usually by cytochrome P450 (P450). P450 1A2 plays a...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章,评审
doi:10.1146/annurev.pharmtox.45.120403.100010
更新日期:2005-01-01 00:00:00
abstract::The beta 3 subtype of adrenaline and noradrenaline receptors has now been extensively characterized at the structural and functional levels. Ligand binding and adenylyl cyclase activation studies helped define a beta-adrenergic profile that is quite distinct from that of the beta 1- and beta 2-adrenergic receptors, bu...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章,评审
doi:10.1146/annurev.pharmtox.37.1.421
更新日期:1997-01-01 00:00:00
abstract::Development of scientific creativity is often tied closely to mentorship. In my case, two years with Julius Axelrod, the sum total of my research training, was transformative. My mentoring generations of graduate students and postdoctoral fellows has been as nurturing for me as it has been for them. Work in our lab ov...
journal_title:Annual review of pharmacology and toxicology
pub_type: 历史文章,杂志文章
doi:10.1146/annurev-pharmtox-010716-104511
更新日期:2017-01-06 00:00:00
abstract::γ-Secretases are a group of widely expressed, intramembrane-cleaving proteases involved in many physiological processes. Their clinical relevance comes from their involvement in Alzheimer's disease, cancer, and other disorders. A clinical trial with the wide-spectrum γ-secretase inhibitor semagacestat has, however, de...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章,评审
doi:10.1146/annurev-pharmtox-010814-124309
更新日期:2015-01-01 00:00:00
abstract::Oligonucleotides (ONs) can interfere with biomolecules representing the entire extended central dogma. Antisense gapmer, steric block, splice-switching ONs, and short interfering RNA drugs have been successfully developed. Moreover, antagomirs (antimicroRNAs), microRNA mimics, aptamers, DNA decoys, DNAzymes, synthetic...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章,评审
doi:10.1146/annurev-pharmtox-010818-021050
更新日期:2019-01-06 00:00:00
abstract::Numerous lines of evidence demonstrate that calpains, a family of 14 Ca(2+)-activated neutral cysteine proteases, are involved in oncotic cell death in a variety of models. At this time, the biochemistry of most calpains and the specific roles of different calpains in physiology and pathology remain to be determined. ...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章,评审
doi:10.1146/annurev.pharmtox.44.101802.121804
更新日期:2004-01-01 00:00:00
abstract::Cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) are two Ca(2+) messengers derived from NAD and NADP, respectively. Although NAADP is a linear molecule, structurally distinct from the cyclic cADPR, it is synthesized by similar enzymes, ADP-ribosyl cyclase and its homolog, CD38. The c...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章,评审
doi:10.1146/annurev.pharmtox.41.1.317
更新日期:2001-01-01 00:00:00
abstract::Billions of US dollars are invested every year by the pharmaceutical industry in drug development, with the aim of introducing new drugs that are effective and have minimal side effects. Thirty percent of in-pipeline drugs are excluded in an early phase of preclinical and clinical screening owing to cardiovascular saf...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章,评审
doi:10.1146/annurev-pharmtox-010617-053110
更新日期:2018-01-06 00:00:00
abstract::CB1 and CB2 cannabinoid receptors are the primary targets of endogenous cannabinoids (endocannabinoids). These G protein-coupled receptors play an important role in many processes, including metabolic regulation, craving, pain, anxiety, bone growth, and immune function. Cannabinoid receptors can be engaged directly by...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章,评审
doi:10.1146/annurev.pharmtox.46.120604.141254
更新日期:2006-01-01 00:00:00
abstract::G protein-coupled receptors (GPCRs) represent a major class of proteins in the genome of many species, including humans. In addition to the mapping of a number of human disorders to regions of the genome containing GPCRs, a growing body of literature has documented frequently occurring variations (i.e. polymorphisms) ...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章,评审
doi:10.1146/annurev.pharmtox.41.1.593
更新日期:2001-01-01 00:00:00
abstract::Kv7 channels (Kv7.1-7.5) are voltage-gated K+ channels that can be modulated by five β-subunits (KCNE1-5). Kv7.1-KCNE1 channels produce the slow-delayed rectifying K+ current, IKs, which is important during the repolarization phase of the cardiac action potential. Kv7.2-7.5 are predominantly neuronally expressed and c...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章
doi:10.1146/annurev-pharmtox-010919-023645
更新日期:2021-01-06 00:00:00
abstract::Cyclooxygenase (COX), first purified in 1976 and cloned in 1988, is the key enzyme in the synthesis of prostaglandins (PGs) from arachidonic acid. In 1991, several laboratories identified a product from a second gene with COX activity and called it COX-2. However, COX-2 was inducible, and the inducing stimuli included...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章,评审
doi:10.1146/annurev.pharmtox.38.1.97
更新日期:1998-01-01 00:00:00
abstract::Parkinson's disease (PD) is a chronic, progressive, disabling neurodegenerative disorder that begins in mid to late life and is characterized by motor impairment, autonomic dysfunction, and, in many, psychological and cognitive changes. Recent advances have helped delineate pathogenetic mechanisms, yet the cause of PD...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章,评审
doi:10.1146/annurev-pharmtox-011613-135937
更新日期:2014-01-01 00:00:00
abstract::The RNA polymerase I (Pol I) transcription machinery in the nucleolus is the key convergence point that collects and integrates a vast array of information from cellular signaling cascades to regulate ribosome production that in turn guides cell growth and proliferation. Cancer cells commonly harbor mutations that ina...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章,评审
doi:10.1146/annurev.pharmtox.010909.105844
更新日期:2010-01-01 00:00:00
abstract::The Risk Assessment Committee of the European Chemicals Agency issued an opinion on classifying titanium dioxide (TiO2) as a suspected human carcinogen upon inhalation. Recent animal studies indicate that TiO2 may be carcinogenic through the oral route. There is considerable uncertainty on the carcinogenicity of TiO2,...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章
doi:10.1146/annurev-pharmtox-101419-100049
更新日期:2021-01-06 00:00:00
abstract::Chemokines are the largest family of cytokines in human immunophysiology. These proteins are defined by four invariant cysteines and are categorized based on the sequence around the first two cysteines, which leads to two major and two minor subfamilies. Chemokines function by activating specific G protein-coupled rec...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章,评审
doi:10.1146/annurev.pharmtox.42.091901.115838
更新日期:2002-01-01 00:00:00
abstract::The realization that there exists a multimembered family of cation channels with structural similarity to Drosophila's Trp channel emerged during the second half of the 1990s. In mammals, depending on the species, the TRP family counts 29 or 30 members which has been subdivided into 6 subfamilies on the basis of seque...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章,评审
doi:10.1146/annurev.pharmtox.48.113006.094928
更新日期:2009-01-01 00:00:00
abstract::Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase (MAPK) kinase kinase of the c-Jun N-terminal kinase (JNK) and p38 MAPK pathways. ASK1 is preferentially activated by various cytotoxic stressors and plays pivotal roles in a wide variety of cellular response to them. Recent analyses of A...
journal_title:Annual review of pharmacology and toxicology
pub_type: 杂志文章,评审
doi:10.1146/annurev.pharmtox.48.113006.094606
更新日期:2008-01-01 00:00:00