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Isomeric and Conformational Analysis of Small Drug and Drug-Like Molecules by Ion Mobility-Mass Spectrometry (IM-MS).
Phillips ST, Dodds JN, May JC, McLean JA
(2019) Methods Mol Biol 1939: 161-178
MeSH Terms: Algorithms, Amino Acids, Carbohydrates, Ion Mobility Spectrometry, Isomerism, Mass Spectrometry, Molecular Conformation, Pharmaceutical Preparations, Small Molecule Libraries, Software
Show Abstract · Added August 7, 2019
This chapter provides a broad overview of ion mobility-mass spectrometry (IM-MS) and its applications in separation science, with a focus on pharmaceutical applications. A general overview of fundamental ion mobility (IM) theory is provided with descriptions of several contemporary instrument platforms which are available commercially (i.e., drift tube and traveling wave IM). Recent applications of IM-MS toward the evaluation of structural isomers are highlighted and placed in the context of both a separation and characterization perspective. We conclude this chapter with a guided reference protocol for obtaining routine IM-MS spectra on a commercially available uniform-field IM-MS.
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Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study.
Salem JE, Manouchehri A, Moey M, Lebrun-Vignes B, Bastarache L, Pariente A, Gobert A, Spano JP, Balko JM, Bonaca MP, Roden DM, Johnson DB, Moslehi JJ
(2018) Lancet Oncol 19: 1579-1589
MeSH Terms: Adult, Adverse Drug Reaction Reporting Systems, Aged, Aged, 80 and over, Antineoplastic Agents, Immunological, Bayes Theorem, Cardiotoxicity, Cardiovascular Diseases, Databases, Factual, Female, Humans, Immunotherapy, Male, Middle Aged, Pharmacovigilance, Retrospective Studies, Risk Assessment, Risk Factors, Time Factors
Show Abstract · Added December 13, 2018
BACKGROUND - Immune checkpoint inhibitors (ICIs) have substantially improved clinical outcomes in multiple cancer types and are increasingly being used in early disease settings and in combinations of different immunotherapies. However, ICIs can also cause severe or fatal immune-related adverse-events (irAEs). We aimed to identify and characterise cardiovascular irAEs that are significantly associated with ICIs.
METHODS - In this observational, retrospective, pharmacovigilance study, we used VigiBase, WHO's global database of individual case safety reports, to compare cardiovascular adverse event reporting in patients who received ICIs (ICI subgroup) with this reporting in the full database. This study included all cardiovascular irAEs classified by group queries according to the Medical Dictionary for Regulatory Activities, between inception on Nov 14, 1967, and Jan 2, 2018. We evaluated the association between ICIs and cardiovascular adverse events using the reporting odds ratio (ROR) and the information component (IC). IC is an indicator value for disproportionate Bayesian reporting that compares observed and expected values to find associations between drugs and adverse events. IC is the lower end of the IC 95% credibility interval, and an IC value of more than zero is deemed significant. This study is registered with ClinicalTrials.gov, number NCT03387540.
FINDINGS - We identified 31 321 adverse events reported in patients who received ICIs and 16 343 451 adverse events reported in patients treated with any drugs (full database) in VigiBase. Compared with the full database, ICI treatment was associated with higher reporting of myocarditis (5515 reports for the full database vs 122 for ICIs, ROR 11·21 [95% CI 9·36-13·43]; IC 3·20), pericardial diseases (12 800 vs 95, 3·80 [3·08-4·62]; IC 1·63), and vasculitis (33 289 vs 82, 1·56 [1·25-1·94]; IC 0·03), including temporal arteritis (696 vs 18, 12·99 [8·12-20·77]; IC 2·59) and polymyalgia rheumatica (1709 vs 16, 5·13 [3·13-8·40]; IC 1·33). Pericardial diseases were reported more often in patients with lung cancer (49 [56%] of 87 patients), whereas myocarditis (42 [41%] of 103 patients) and vasculitis (42 [60%] of 70 patients) were more commonly reported in patients with melanoma (χ test for overall subgroup comparison, p<0·0001). Vision was impaired in five (28%) of 18 patients with temporal arteritis. Cardiovascular irAEs were severe in the majority of cases (>80%), with death occurring in 61 (50%) of 122 myocarditis cases, 20 (21%) of 95 pericardial disease cases, and five (6%) of 82 vasculitis cases (χ test for overall comparison between pericardial diseases, myocarditis, and vasculitis, p<0·0001).
INTERPRETATION - Treatment with ICIs can lead to severe and disabling inflammatory cardiovascular irAEs soon after commencement of therapy. In addition to life-threatening myocarditis, these toxicities include pericardial diseases and temporal arteritis with a risk of blindness. These events should be considered in patient care and in combination clinical trial designs (ie, combinations of different immunotherapies as well as immunotherapies and chemotherapy).
FUNDING - The Cancer Institut Thématique Multi-Organisme of the French National Alliance for Life and Health Sciences (AVIESAN) Plan Cancer 2014-2019; US National Cancer Institute, National Institutes of Health; the James C. Bradford Jr. Melanoma Fund; and the Melanoma Research Foundation.
Copyright © 2018 Elsevier Ltd. All rights reserved.
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19 MeSH Terms
Immune Checkpoint Inhibitor-Associated Myositis.
Anquetil C, Salem JE, Lebrun-Vignes B, Johnson DB, Mammen AL, Stenzel W, Léonard-Louis S, Benveniste O, Moslehi JJ, Allenbach Y
(2018) Circulation 138: 743-745
MeSH Terms: Adult, Adverse Drug Reaction Reporting Systems, Aged, Aged, 80 and over, Antineoplastic Agents, Immunological, Databases, Factual, Female, Humans, Immunotherapy, Male, Middle Aged, Myositis, Pharmacovigilance, Prognosis, Risk Assessment, Risk Factors, Time Factors
Added December 13, 2018
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Individual differences in dopamine D receptor availability correlate with reward valuation.
Dang LC, Samanez-Larkin GR, Castrellon JJ, Perkins SF, Cowan RL, Zald DH
(2018) Cogn Affect Behav Neurosci 18: 739-747
MeSH Terms: Adult, Anticipation, Psychological, Benzamides, Brain, Brain Mapping, Cerebrovascular Circulation, Female, Fluorine Radioisotopes, Humans, Individuality, Magnetic Resonance Imaging, Male, Oxygen, Positron-Emission Tomography, Radiopharmaceuticals, Receptors, Dopamine D2, Reward
Show Abstract · Added April 15, 2019
Reward valuation, which underlies all value-based decision-making, has been associated with dopamine function in many studies of nonhuman animals, but there is relatively less direct evidence for an association in humans. Here, we measured dopamine D receptor (DRD2) availability in vivo in humans to examine relations between individual differences in dopamine receptor availability and neural activity associated with a measure of reward valuation, expected value (i.e., the product of reward magnitude and the probability of obtaining the reward). Fourteen healthy adult subjects underwent PET with [F]fallypride, a radiotracer with strong affinity for DRD2, and fMRI (on a separate day) while performing a reward valuation task. [F]fallypride binding potential, reflecting DRD2 availability, in the midbrain correlated positively with neural activity associated with expected value, specifically in the left ventral striatum/caudate. The present results provide in vivo evidence from humans showing midbrain dopamine characteristics are associated with reward valuation.
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17 MeSH Terms
Macrophage-Targeted Therapeutics for Metabolic Disease.
Peterson KR, Cottam MA, Kennedy AJ, Hasty AH
(2018) Trends Pharmacol Sci 39: 536-546
MeSH Terms: Drug Delivery Systems, Gene Expression, Humans, Macrophages, Metabolic Diseases, Molecular Targeted Therapy, Pharmaceutical Preparations
Show Abstract · Added March 26, 2019
Macrophages are cells of the innate immune system that are resident in all tissues, including metabolic organs such as the liver and adipose tissue (AT). Because of their phenotypic flexibility, they play beneficial roles in tissue homeostasis, but they also contribute to the progression of metabolic disease. Thus, they are ideal therapeutic targets for diseases such as insulin resistance (IR), nonalcoholic fatty liver disease (NAFLD), and atherosclerosis. Recently, discoveries in the area of drug delivery have facilitated phenotype-specific targeting of macrophages. In this review we discuss advances in potential therapeutics for metabolic diseases via macrophage-specific delivery. We highlight micro- and nanoparticles, liposomes, and oligopeptide complexes, and how they can be used to alter macrophage phenotype for a more metabolically favorable tissue environment.
Published by Elsevier Ltd.
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Genetics of the patent ductus arteriosus (PDA) and pharmacogenetics of PDA treatment.
Lewis TR, Shelton EL, Van Driest SL, Kannankeril PJ, Reese J
(2018) Semin Fetal Neonatal Med 23: 232-238
MeSH Terms: Acetaminophen, Animals, Disease Models, Animal, Ductus Arteriosus, Patent, Genetic Predisposition to Disease, Humans, Ibuprofen, Indomethacin, Infant, Newborn, Infant, Premature, Pharmacogenetics
Show Abstract · Added March 31, 2018
Patent ductus arteriosus (PDA) is a frequent, complex, and difficult to treat clinical syndrome among preterm infants in the neonatal intensive care unit. In addition to known clinical risk factors, there are emerging data about genetic predisposition to PDA in both animal and human models. Clinical response and toxicity from drugs used to treat PDA are highly variable. Developmental and genetic aspects of pharmacokinetics and pharmacodynamics influence exposure and response to pharmacologic therapies. Given the variable efficacy and toxicity of known drug therapies, novel therapeutic targets for PDA treatment offer the promise of precision medicine. This review addresses the known genetic contributions to prolonged ductal patency, variability in response to drug therapy for PDA, and potential novel drug targets for future PDA treatment discovery.
Copyright © 2018 Elsevier Ltd. All rights reserved.
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Evaluation of the novel TSPO radiotracer 2-(7-butyl-2-(4-(2-([F]fluoroethoxy)phenyl)-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide in a preclinical model of neuroinflammation.
Tang D, Fujinaga M, Hatori A, Zhang Y, Yamasaki T, Xie L, Mori W, Kumata K, Liu J, Manning HC, Huang G, Zhang MR
(2018) Eur J Med Chem 150: 1-8
MeSH Terms: Animals, Disease Models, Animal, Dose-Response Relationship, Drug, Fluorine Radioisotopes, Humans, Inflammation, Ischemia, Male, Mice, Molecular Probes, Molecular Structure, Positron-Emission Tomography, Pyrazoles, Pyrimidines, Radioactive Tracers, Radiopharmaceuticals, Rats, Rats, Sprague-Dawley, Receptors, GABA, Structure-Activity Relationship, Tissue Distribution
Show Abstract · Added March 22, 2018
Translocator Protein (18 kDa, TSPO) is regarded as a useful biomarker for neuroinflammation imaging. TSPO PET imaging could be used to understand the role of neuroinflammation in brain diseases and as a tool for evaluating novel therapeutic effects. As a promising TSPO probe, [F]DPA-714 is highly specific and offers reliable quantification of TSPO in vivo. In this study, we further radiosynthesized and evaluated another novel TSPO probe, 2-(7-butyl-2-(4-(2-[F]fluoroethoxy)phenyl)-5-methylpyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide ([F]VUIIS1018A), which features a 700-fold higher binding affinity for TSPO than that of [F]DPA-714. We evaluated the performance of [F]VUIIS1018A using dynamic in vivo PET imaging, radiometabolite analysis, in vitro autoradiography assays, biodistribution analysis, and blocking assays. In vivo study using this probe demonstrated high signal-to-noise ratio, binding potential (BP), and binding specificity in preclinical neuroinflammation studies. Taken together, these findings indicate that [F]VUIIS1018A may serve as a novel TSPO PET probe for neuroinflammation imaging.
Copyright © 2018. Published by Elsevier Masson SAS.
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21 MeSH Terms
Research Directions in the Clinical Implementation of Pharmacogenomics: An Overview of US Programs and Projects.
Volpi S, Bult CJ, Chisholm RL, Deverka PA, Ginsburg GS, Jacob HJ, Kasapi M, McLeod HL, Roden DM, Williams MS, Green ED, Rodriguez LL, Aronson S, Cavallari LH, Denny JC, Dressler LG, Johnson JA, Klein TE, Leeder JS, Piquette-Miller M, Perera M, Rasmussen-Torvik LJ, Rehm HL, Ritchie MD, Skaar TC, Wagle N, Weinshilboum R, Weitzel KW, Wildin R, Wilson J, Manolio TA, Relling MV
(2018) Clin Pharmacol Ther 103: 778-786
MeSH Terms: Humans, Pharmacogenetics, Precision Medicine, Research, United States
Show Abstract · Added March 14, 2018
Response to a drug often differs widely among individual patients. This variability is frequently observed not only with respect to effective responses but also with adverse drug reactions. Matching patients to the drugs that are most likely to be effective and least likely to cause harm is the goal of effective therapeutics. Pharmacogenomics (PGx) holds the promise of precision medicine through elucidating the genetic determinants responsible for pharmacological outcomes and using them to guide drug selection and dosing. Here we survey the US landscape of research programs in PGx implementation, review current advances and clinical applications of PGx, summarize the obstacles that have hindered PGx implementation, and identify the critical knowledge gaps and possible studies needed to help to address them.
© 2018 American Society for Clinical Pharmacology and Therapeutics.
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5 MeSH Terms
Benefit of Preemptive Pharmacogenetic Information on Clinical Outcome.
Roden DM, Van Driest SL, Mosley JD, Wells QS, Robinson JR, Denny JC, Peterson JF
(2018) Clin Pharmacol Ther 103: 787-794
MeSH Terms: Drug Prescriptions, Genetic Variation, Genotype, Humans, Pharmacogenetics, Pharmacogenomic Testing
Show Abstract · Added March 14, 2018
The development of new knowledge around the genetic determinants of variable drug action has naturally raised the question of how this new knowledge can be used to improve the outcome of drug therapy. Two broad approaches have been taken: a point-of-care approach in which genotyping for specific variant(s) is undertaken at the time of drug prescription, and a preemptive approach in which multiple genetic variants are typed in an individual patient and the information archived for later use when a drug with a "pharmacogenetic story" is prescribed. This review addresses the current state of implementation, the rationale for these approaches, and barriers that must be overcome. Benefits to pharmacogenetic testing are only now being defined and will be discussed.
© 2018 American Society for Clinical Pharmacology and Therapeutics.
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Sulfenylation of Human Liver and Kidney Microsomal Cytochromes P450 and Other Drug-Metabolizing Enzymes as a Response to Redox Alteration.
Albertolle ME, Phan TTN, Pozzi A, Guengerich FP
(2018) Mol Cell Proteomics 17: 889-900
MeSH Terms: Animals, Biocatalysis, Cysteine, Cytochrome P-450 Enzyme System, Humans, Hydrogen Peroxide, Kidney, Mice, Transgenic, Microsomes, Liver, Oxidation-Reduction, Pharmaceutical Preparations, Recombinant Proteins, Staining and Labeling, Sulfenic Acids, Sulfhydryl Compounds
Show Abstract · Added March 14, 2018
The lumen of the endoplasmic reticulum (ER) provides an oxidizing environment to aid in the formation of disulfide bonds, which is tightly regulated by both antioxidant proteins and small molecules. On the cytoplasmic side of the ER, cytochrome P450 (P450) proteins have been identified as a superfamily of enzymes that are important in the formation of endogenous chemicals as well as in the detoxication of xenobiotics. Our previous report described oxidative inhibition of P450 Family 4 enzymes via oxidation of the heme-thiolate cysteine to a sulfenic acid (-SOH) (Albertolle, M. E. (2017) 292, 11230-11242). Further proteomic analyses of murine kidney and liver microsomes led to the finding that a number of other drug-metabolizing enzymes located in the ER are also redox-regulated in this manner. We expanded our analysis of sulfenylated enzymes to human liver and kidney microsomes. Evaluation of the sulfenylation, catalytic activity, and spectral properties of P450s 1A2, 2C8, 2D6, and 3A4 led to the identification of two classes of redox sensitivity in P450 enzymes: heme-thiolate-sensitive and thiol-insensitive. These findings provide evidence for a mammalian P450 regulatory mechanism, which may also be relevant to other drug-metabolizing enzymes. (Data are available via ProteomeXchange with identifier PXD007913.).
© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
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