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Results: 1 to 10 of 11

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The Influence of Big (Clinical) Data and Genomics on Precision Medicine and Drug Development.
Denny JC, Van Driest SL, Wei WQ, Roden DM
(2018) Clin Pharmacol Ther 103: 409-418
MeSH Terms: Big Data, Drug Repositioning, Electronic Health Records, Humans, Pharmacogenetics, Pharmacology, Clinical, Precision Medicine, Randomized Controlled Trials as Topic
Show Abstract · Added March 14, 2018
Drug development continues to be costly and slow, with medications failing due to lack of efficacy or presence of toxicity. The promise of pharmacogenomic discovery includes tailoring therapeutics based on an individual's genetic makeup, rational drug development, and repurposing medications. Rapid growth of large research cohorts, linked to electronic health record (EHR) data, fuels discovery of new genetic variants predicting drug action, supports Mendelian randomization experiments to show drug efficacy, and suggests new indications for existing medications. New biomedical informatics and machine-learning approaches advance the ability to interpret clinical information, enabling identification of complex phenotypes and subpopulations of patients. We review the recent history of use of "big data" from EHR-based cohorts and biobanks supporting these activities. Future studies using EHR data, other information sources, and new methods will promote a foundation for discovery to more rapidly advance precision medicine.
© 2017 American Society for Clinical Pharmacology and Therapeutics.
0 Communities
1 Members
0 Resources
8 MeSH Terms
Beyond traditional pharmacology: new tools and approaches.
Gurevich EV, Gurevich VV
(2015) Br J Pharmacol 172: 3229-41
MeSH Terms: Animals, Biological Products, Cell- and Tissue-Based Therapy, Genetic Therapy, Humans, Pharmacology, Protein Engineering, Signal Transduction
Show Abstract · Added February 12, 2015
Traditional pharmacology is defined as the science that deals with drugs and their actions. While small molecule drugs have clear advantages, there are many cases where they have proved to be ineffective, prone to unacceptable side effects, or where due to a particular disease aetiology they cannot possibly be effective. A dominant feature of the small molecule drugs is their single mindedness: they provide either continuous inhibition or continuous activation of the target. Because of that, these drugs tend to engage compensatory mechanisms leading to drug tolerance, drug resistance or, in some cases, sensitization and consequent loss of therapeutic efficacy over time and/or unwanted side effects. Here we discuss new and emerging therapeutic tools and approaches that have potential for treating the majority of disorders for which small molecules are either failing or cannot be developed. These new tools include biologics, such as recombinant hormones and antibodies, as well as approaches involving gene transfer (gene therapy and genome editing) and the introduction of specially designed self-replicating cells. It is clear that no single method is going to be a 'silver bullet', but collectively, these novel approaches hold promise for curing practically every disorder.
© 2015 The British Pharmacological Society.
0 Communities
1 Members
0 Resources
8 MeSH Terms
Electronic medical records as a tool in clinical pharmacology: opportunities and challenges.
Roden DM, Xu H, Denny JC, Wilke RA
(2012) Clin Pharmacol Ther 91: 1083-86
MeSH Terms: Electronic Health Records, Genetics, Humans, Pharmacogenetics, Pharmacology, Clinical, Phenotype, United States
Show Abstract · Added March 7, 2014
The development and increasing sophistication of electronic medical record (EMR) systems hold the promise of not only improving patient care but also providing unprecedented opportunities for discovery in the fields of basic, translational, and implementation sciences. Clinical pharmacology research in the EMR environment has only recently started to become a reality, with EMRs becoming increasingly populated, methods to mine drug response and other phenotypes becoming more sophisticated, and links being established with DNA repositories.
0 Communities
2 Members
0 Resources
7 MeSH Terms
An interview with P. Jeffrey Conn.
Conn PJ
(2012) Trends Pharmacol Sci 33: 119-21
MeSH Terms: Humans, Mental Disorders, Nervous System Diseases, Pharmacology
Added February 19, 2015
0 Communities
1 Members
0 Resources
4 MeSH Terms
Neurotherapeutics.
Smith GS, Li X, Conn PJ
(2012) Neuropsychopharmacology 37: 1-3
MeSH Terms: Animals, Central Nervous System Diseases, Humans, Neuropharmacology, Psychopharmacology
Added February 19, 2015
0 Communities
1 Members
0 Resources
5 MeSH Terms
Orphans in the human cytochrome P450 superfamily: approaches to discovering functions and relevance in pharmacology.
Guengerich FP, Cheng Q
(2011) Pharmacol Rev 63: 684-99
MeSH Terms: Animals, Biochemistry, Cytochrome P-450 Enzyme System, Humans, Isoenzymes, Organ Specificity, Pharmacology, Substrate Specificity
Show Abstract · Added March 7, 2014
As a result of technical advances in recombinant DNA technology and nucleotide sequencing, entire genome sequences have become available in the past decade and offer potential in understanding diseases. However, a central problem in the biochemical sciences is that the functions of only a fraction of the genes/proteins are known, and this is also an issue in pharmacology. This review is focused on issues related to the functions of cytochrome P450 (P450) enzymes. P450 functions can be categorized in several groups: 1) Some P450s have critical roles in the metabolism of endogenous substrates (e.g., sterols and fat-soluble vitamins). 2) Some P450s are not generally critical to normal physiology but function in relatively nonselective protection from the many xenobiotic chemicals to which mammals (including humans) are exposed in their diets [as well as more anthropomorphic chemicals (e.g., drugs, pesticides)]. 3) Some P450s have not been extensively studied and are termed "orphans" here. With regard to elucidation of any physiological functions of the orphan P450s, the major subject of this review, it is clear that simple trial-and-error approaches with individual substrate candidates will not be very productive in addressing questions about function. A series of liquid chromatography/mass spectrometry/informatics approaches are discussed, along with some successes with both human and bacterial P450s. Current information on what are still considered "orphan" P450s is presented. The potential for application of some of these approaches to other enzyme systems is also discussed.
0 Communities
1 Members
0 Resources
8 MeSH Terms
Adequacy of representation of the National Drug File Reference Terminology Physiologic Effects reference hierarchy for commonly prescribed medications.
Rosenbloom ST, Awad J, Speroff T, Elkin PL, Rothman R, Spickard A, Peterson J, Bauer BA, Wahner-Roedler DL, Lee M, Gregg WM, Johnson KB, Jirjis J, Erlbaum MS, Carter JS, Lincoln MJ, Brown SH
(2003) AMIA Annu Symp Proc : 569-78
MeSH Terms: Drug Therapy, Humans, Models, Biological, Pharmaceutical Preparations, Pharmacology, Physiology, Vocabulary, Controlled
Show Abstract · Added December 10, 2013
The National Drug File Reference Terminology contains a novel reference hierarchy to describe physiologic effects (PE) of drugs. The PE reference hierarchy contains 1697 concepts arranged into two broad categories; organ specific and generalized systemic effects. This investigation evaluated the appropriateness of the PE concepts for classifying a random selection of commonly prescribed medications. Ten physician reviewers classified the physiologic effects of ten drugs and rated the accuracy of the selected term. Inter reviewer agreement, overall confidence, and concept frequencies were assessed and were correlated with the complexity of the drug's known physiologic effects. In general, agreement between reviewers was fair to moderate (kappa 0.08-0.49). The physiologic effects modeled became more disperse with drugs having and inducing multiple physiologic processes. Complete modeling of all physiologic effects was limited by reviewers focusing on different physiologic processes. The reviewers were generally comfortable with the accuracy of the concepts selected. Overall, the PE reference hierarchy was useful for physician reviewers classifying the physiologic effects of drugs. Ongoing evolution of the PE reference hierarchy as it evolves should take into account the experiences of our reviewers.
0 Communities
2 Members
0 Resources
7 MeSH Terms
Clinical pharmacology & therapeutics--an update.
Stein CM
(2003) Clin Pharmacol Ther 73: 1-3
MeSH Terms: Authorship, Conflict of Interest, Forecasting, Journalism, Medical, Pharmacology, Research Support as Topic, United States
Added December 10, 2013
0 Communities
1 Members
0 Resources
7 MeSH Terms
Organization, management and operation of contemporary academic mass spectrometry service facilities.
Wood KV, Hachey DL
(2000) J Mass Spectrom 35: 1157-64
MeSH Terms: Chemistry, Analytic, Chemistry, Pharmaceutical, Indiana, Mass Spectrometry, Molecular Biology, Pharmacology, Tennessee, Universities
Show Abstract · Added March 20, 2014
The rapid evolution of mass spectrometry in the past 15 years has moved mass spectrometry facilities from the traditional model in which instruments were located in and used for a single department's samples to a distributed model servicing entire universities. In this paper we describe two such shared instrument facilities that have evolved from a base in a single department to facilities that service a broad clientele. The Purdue University Campus-wide Mass Spectrometry Center (CWMSC) is a decentralized facility with multiple sites on campus. The CWMSC is a limited-access facility in which samples are run by service facility personnel in close cooperation with investigators. The Vanderbilt University Mass Spectrometry Research Center (VU-MSRC) is a centralized facility in the medical school that provides services to the university at large. The VU-MSRC is an open-access facility in which users are expected to prepare and analyze their own samples under the guidance of a trained operator. Perhaps the most significant benefit achieved by these models has been the minimization of academic barriers and the resultant intellectual cross-fertilization that has greatly enriched research at institutions where this approach has been adopted. The advantages and limitations of both models are discussed in terms of the traditional academic paradigm of service, research and education.
0 Communities
1 Members
0 Resources
8 MeSH Terms
The role of clinical pharmacology in molecular genetics.
Robertson D
(1997) Int J Clin Pharmacol Ther 35: 135-41
MeSH Terms: Adult, Blood Pressure, Dopamine, Dopamine beta-Hydroxylase, Humans, Hypotension, Orthostatic, Male, Neurons, Norepinephrine, Pharmacology, Clinical, Phenotype, Receptors, Adrenergic, Sympathetic Nervous System, Synaptic Transmission
Show Abstract · Added December 10, 2013
PROBLEM - Discovering the causes of unusual phenotypes in human subjects is an important aspect of patient-oriented research.
MATERIAL - The tools of clinical pharmacology are uniquely useful in addressing these problems. PATIENTS, SUBJECTS, OR CASE HISTORIES: We evaluated a 42-year-old patient with lifelong orthostatic hypotension and ptosis of the eyelids. He underwent a series of biochemical, physiological, and pharmacological tests outlined in this article.
RESULTS - These studies indicated that sympathetic innervation was intact but that the sympathetic neurotransmitter was dopamine rather than norepinephrine. These results demonstrated that dopamine-beta-hydroxylase deficiency underlies the clinical abnormalities of this patient.
CONCLUSION - In selected individuals with unusual phenotypes, the techniques of clinical chemistry and clinical pharmacology can define the nature of the defect at almost the resolution of the human genome.
0 Communities
1 Members
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14 MeSH Terms