181 results on '"John G. Gums"'
Search Results
2. Circulating microRNA Biomarkers of Thiazide Response in Hypertension
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Lakshmi Manasa S. Chekka, Marwa Tantawy, Taimour Langaee, Danxin Wang, Rolf Renne, Arlene B. Chapman, John G. Gums, Eric Boerwinkle, Rhonda M. Cooper‐DeHoff, and Julie A. Johnson
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antihypertensive response ,biomarkers ,blood pressure response ,chlorthalidone ,circulating microRNA ,hydrochlorothiazide ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
Background Thiazide diuretics are the second most frequently prescribed class of antihypertensives, but up to 50% of patients with hypertension have minimal antihypertensive response to thiazides. We explored circulating microRNAs (miRNAs) in search of predictive biomarkers of thiazide response. Methods and Results We profiled 754 miRNAs in baseline plasma samples of 36 hypertensive European American adults treated with hydrochlorothiazide, categorized into responders (n=18) and nonresponders (n=18) on the basis of diastolic blood pressure response to hydrochlorothiazide. miRNAs with ≥2.5‐fold differential expression between responders and nonresponders were considered for validation in 3 cohorts (n=50 each): hydrochlorothiazide‐treated European Americans, chlorthalidone‐treated European Americans, and hydrochlorothiazide‐treated Black individuals. Different blood pressure phenotypes including categorical (responder versus nonresponder) and continuous diastolic blood pressure and systolic blood pressure were tested for association with the candidate miRNA expression using multivariate regression analyses adjusting for age, sex, and baseline blood pressure. After quality control, 74 miRNAs were available for screening, 19 of which were considered for validation. In the validation cohort, miR‐193b‐3p and 30d‐5p showed significant associations with continuous SBP or diastolic blood pressure response or both, to hydrochlorothiazide in European Americans at Benjamini‐Hochberg adjusted P
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- 2024
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3. Pairwise comparison of hydrochlorothiazide and chlorthalidone responses among hypertensive patients
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Lakshmi Manasa S. Chekka, Rhonda M. Cooper‐DeHoff, John G. Gums, Arlene B. Chapman, and Julie A. Johnson
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Therapeutics. Pharmacology ,RM1-950 ,Public aspects of medicine ,RA1-1270 - Abstract
Abstract This study conducted a pairwise comparison of antihypertensive and metabolic effects of hydrochlorothiazide (HCTZ) and chlorthalidone (CTD) at 25 mg/day in the same individuals to address the clinical dilemma on preferred thiazide for hypertension (HTN) management. We included 15 African American (AA) and 35 European American (EA) patients with HTN treated with HCTZ and CTD as part of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR‐2 trials, respectively. Mean reduction in systolic/diastolic blood pressure (SBP/DBP) with HCTZ versus CTD was 8/5 versus 16/8 mmHg among EA patients (p
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- 2022
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4. Influence of Genetic West African Ancestry on Metabolomics among Hypertensive Patients
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Mai Mehanna, Caitrin W. McDonough, Steven M. Smith, Yan Gong, John G. Gums, Arlene B. Chapman, Julie A. Johnson, and Rhonda M. Cooper-DeHoff
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African ancestry ,metabolomics ,hypertension ,blood pressure ,Microbiology ,QR1-502 - Abstract
Patients with higher genetic West African ancestry (GWAA) have hypertension (HTN) that is more difficult to treat and have higher rates of cardiovascular diseases (CVD) and differential responses to antihypertensive drugs than those with lower GWAA. The mechanisms underlying these disparities are poorly understood. Using data from 84 ancestry-informative markers in US participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 trials, the GWAA proportion was estimated. Using multivariable linear regression, the baseline levels of 886 metabolites were compared between PEAR participants with GWAA < 45% and those with GWAA ≥ 45% to identify differential metabolites and metabolic clusters. Metabolites with a false discovery rate (FDR) < 0.2 were used to create metabolic clusters, and a cluster analysis was conducted. Differential clusters were then tested for replication in PEAR-2 participants. We identified 353 differential metabolites (FDR < 0.2) between PEAR participants with GWAA < 45% (n = 383) and those with GWAA ≥ 45% (n = 250), which were used to create 24 metabolic clusters. Of those, 13 were significantly different between groups (Bonferroni p < 0.002). Four clusters, plasmalogen and lysoplasmalogen, sphingolipid metabolism and ceramide, cofactors and vitamins, and the urea cycle, were replicated in PEAR-2 (Bonferroni p < 0.0038) and have been previously linked to HTN and CVD. Our findings may give insights into the mechanisms underlying HTN racial disparities.
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- 2022
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5. Genomic Association Analysis Reveals Variants Associated With Blood Pressure Response to Beta‐Blockers in European Americans
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Sonal Singh, Nihal El Rouby, Caitrin W. McDonough, Yan Gong, Kent R. Bailey, Eric Boerwinkle, Arlene B. Chapman, John G. Gums, Stephen T. Turner, Rhonda M. Cooper‐DeHoff, and Julie A. Johnson
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Therapeutics. Pharmacology ,RM1-950 ,Public aspects of medicine ,RA1-1270 - Abstract
European Americans (EA) have a better antihypertensive response to β‐blockers when compared with African Americans, albeit with some variability. We undertook a genomewide association study to elucidate the underlying genetic determinants in EA contributing to this variability in blood pressure (BP) response. A discovery genomewide association study of change in BP post–metoprolol treatment was performed in EA participants (n = 201) from the Pharmacogenomic Evaluation of Antihypertensive Responses‐2 (PEAR‐2) study and tested for replication in the atenolol‐treated EA from the PEAR study (n = 233). Rs294610 in the FGD5, which encodes for FYVE, RhoGEF and PH Domain Containing 5, (expression quantitative trait loci for FGD5 in the small intestine) was significantly associated with increased diastolic BP response to β‐blockers in the PEAR‐2 study (P = 3.41 × 10−6, β = −2.70) and replicated (P = 0.01, β = −1.17) in the PEAR study. Post–meta‐analysis of these studies, an additional single nucleotide polymorphism rs45545233 in the SLC4A1, encoding for Solute Carrier Family 4 Member 1, (expression quantitative trait loci for dual specificity phosphatase 3 in the artery tibial) was identified that was significantly associated with a poor response to β‐blockers (P = 3.43 × 10−6, β = 4.57) and was replicated in the atenolol add‐on cohort (P = 0.007, β = 4.97). We identified variants in FGD5 and SLC4A1, which have been previously cited as candidate genes for hypertension, to be associated with a β‐blocker BP response in EA. Further elucidation is warranted of the underlying mechanisms of these variants and genes by which they influence the BP response to β‐blockers.
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- 2019
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6. Blood pressure signature genes and blood pressure response to thiazide diuretics: results from the PEAR and PEAR-2 studies
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Ana Caroline C. Sá, Amy Webb, Yan Gong, Caitrin W. McDonough, Mohamed H. Shahin, Somnath Datta, Taimour Y. Langaee, Stephen T. Turner, Amber L. Beitelshees, Arlene B. Chapman, Eric Boerwinkle, John G. Gums, Steven E. Scherer, Rhonda M. Cooper-DeHoff, Wolfgang Sadee, and Julie A. Johnson
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Pharmacogenomics ,Hypertension ,Thiazide diuretics ,Personalized medicine ,RNA-Seq ,eQTL ,Internal medicine ,RC31-1245 ,Genetics ,QH426-470 - Abstract
Abstract Background Recently, 34 genes had been associated with differential expression relative to blood pressure (BP)/ hypertension (HTN). We hypothesize that some of the genes associated with BP/HTN are also associated with BP response to antihypertensive treatment with thiazide diuretics. Methods We assessed these 34 genes for association with differential expression to BP response to thiazide diuretics with RNA sequencing in whole blood samples from 150 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 studies. PEAR white and PEAR-2 white and black participants (n = 50 for each group) were selected based on the upper and lower quartile of BP response to hydrochlorothiazide (HCTZ) and to chlorthalidone. Results FOS, DUSP1 and PPP1R15A were differentially expressed across all cohorts (meta-analysis p-value
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- 2018
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7. Metabolomics Signature of Plasma Renin Activity and Linkage with Blood Pressure Response to Beta Blockers and Thiazide Diuretics in Hypertensive European American Patients
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Mai Mehanna, Caitrin W. McDonough, Steven M. Smith, Yan Gong, John G. Gums, Arlene B. Chapman, Julie A. Johnson, Lauren McIntyre, and Rhonda M. Cooper-DeHoff
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plasma renin activity ,metabolomics ,hypertension ,blood pressure ,Microbiology ,QR1-502 - Abstract
Plasma renin activity (PRA) is a predictive biomarker of blood pressure (BP) response to antihypertensives in European–American hypertensive patients. We aimed to identify the metabolic signatures of baseline PRA and the linkages with BP response to β-blockers and thiazides. Using data from the Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) trial, multivariable linear regression adjusting for age, sex and baseline systolic-BP (SBP) was performed on European–American individuals treated with metoprolol (n = 198) and chlorthalidone (n = 181), to test associations between 856 metabolites and baseline PRA. Metabolites with a false discovery rate (FDR) < 0.05 or p < 0.01 were tested for replication in 463 European–American individuals treated with atenolol or hydrochlorothiazide. Replicated metabolites were then tested for validation based on the directionality of association with BP response. Sixty-three metabolites were associated with baseline PRA, of which nine, including six lipids, were replicated. Of those replicated, two metabolites associated with higher baseline PRA were validated: caprate was associated with greater metoprolol SBP response (β = −1.7 ± 0.6, p = 0.006) and sphingosine-1-phosphate was associated with reduced hydrochlorothiazide SBP response (β = 7.6 ± 2.8, p = 0.007). These metabolites are clustered with metabolites involved in sphingolipid, phospholipid, and purine metabolic pathways. The identified metabolic signatures provide insights into the mechanisms underlying BP response.
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- 2021
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8. Design and Early Implementation Successes and Challenges of a Pharmacogenetics Consult Clinic
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Meghan J. Arwood, Eric A. Dietrich, Benjamin Q. Duong, D. Max Smith, Kelsey Cook, Amanda Elchynski, Eric I. Rosenberg, Katherine N. Huber, Ying L. Nagoshi, Ashleigh Wright, Jeffrey T. Budd, Neal P. Holland, Edlira Maska, Danielle Panna, Amanda R. Elsey, Larisa H. Cavallari, Kristin Wiisanen, Julie A. Johnson, and John G. Gums
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precision medicine ,pharmacogenetics ,pharmacogenomics ,implementation ,primary care ,internal medicine ,Medicine - Abstract
Pharmacogenetic testing (PGT) is increasingly being used as a tool to guide clinical decisions. This article describes the development of an outpatient, pharmacist-led, pharmacogenetics consult clinic within internal medicine, its workflow, and early results, along with successes and challenges. A pharmacogenetics-trained pharmacist encouraged primary care physicians (PCPs) to refer patients who were experiencing side effects/ineffectiveness from certain antidepressants, opioids, and/or proton pump inhibitors. In clinic, the pharmacist confirmed the need for and ordered CYP2C19 and/or CYP2D6 testing, provided evidence-based pharmacogenetic recommendations to PCPs, and educated PCPs and patients on the results. Operational and clinical metrics were analyzed. In two years, 91 referred patients were seen in clinic (mean age 57, 67% women, 91% European-American). Of patients who received PGT, 77% had at least one CYP2C19 and/or CYP2D6 phenotype that would make conventional prescribing unfavorable. Recommendations suggested that physicians change a medication/dose for 59% of patients; excluding two patients lost to follow-up, 87% of recommendations were accepted. Challenges included PGT reimbursement and referral maintenance. High frequency of actionable results suggests physician education on who to refer was successful and illustrates the potential to reduce trial-and-error prescribing. High recommendation acceptance rate demonstrates the pharmacist’s effectiveness in providing genotype-guided recommendations, emphasizing a successful pharmacist–physician collaboration.
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- 2020
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9. Genome‐Wide Association Approach Identified Novel Genetic Predictors of Heart Rate Response to β‐Blockers
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Mohamed H. Shahin, Daniela J. Conrado, Daniel Gonzalez, Yan Gong, Maximilian T. Lobmeyer, Amber L. Beitelshees, Eric Boerwinkle, John G. Gums, Arlene Chapman, Stephen T. Turner, Rhonda M. Cooper‐DeHoff, and Julie A. Johnson
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atenolol ,heart rate ,metoprolol ,pharmacogenomics ,β‐blockers ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
BackgroundFor many indications, the negative chronotropic effect of β‐blockers is important to their efficacy, yet the heart rate (HR) response to β‐blockers varies. Herein, we sought to use a genome‐wide association approach to identify novel single nucleotide polymorphisms (SNPs) associated with HR response to β‐blockers. Methods and ResultsWe first performed 4 genome‐wide association analyses for HR response to atenolol (a β1‐adrenergic receptor blocker) as: (1) monotherapy or (2) add‐on therapy, in 426 whites and 273 blacks separately from the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) study. A meta‐analysis was then performed between the genome‐wide association analysis performed in PEAR atenolol monotherapy and add‐on therapy, in each race separately, using the inverse variance method assuming fixed effects. From this analysis, SNPs associated with HR response to atenolol at a P
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- 2018
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10. Genome Wide Association Study Identifies the HMGCS2 Locus to be Associated With Chlorthalidone Induced Glucose Increase in Hypertensive Patients
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Sonal Singh, Caitrin W. McDonough, Yan Gong, Wael A. Alghamdi, Meghan J. Arwood, Salma A. Bargal, Leanne Dumeny, Wen‐Yi Li, Mai Mehanna, Bradley Stockard, Guang Yang, Felipe A. de Oliveira, Natalie C. Fredette, Mohamed H. Shahin, Kent R. Bailey, Amber L. Beitelshees, Eric Boerwinkle, Arlene B. Chapman, John G. Gums, Stephen T. Turner, Rhonda M. Cooper‐DeHoff, and Julie A. Johnson
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chlorthalidone ,diabetes mellitus ,genome‐wide association study ,glucose ,hydrochlorothiazide ,hyperglycemia ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
BackgroundThiazide and thiazide‐like diuretics are first‐line medications for treating uncomplicated hypertension. However, their use has been associated with adverse metabolic events, including hyperglycemia and incident diabetes mellitus, with incompletely understood mechanisms. Our goal was to identify genomic variants associated with thiazide‐like diuretic/chlorthalidone‐induced glucose change. Methods and ResultsGenome‐wide analysis of glucose change after treatment with chlorthalidone was performed by race among the white (n=175) and black (n=135) participants from the PEAR‐2 (Pharmacogenomic Evaluation of Antihypertensive Responses‐2). Single‐nucleotide polymorphisms with P
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- 2018
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11. Sphingolipid Metabolic Pathway Impacts Thiazide Diuretics Blood Pressure Response: Insights From Genomics, Metabolomics, and Lipidomics
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Mohamed H. Shahin, Yan Gong, Reginald F. Frye, Daniel M. Rotroff, Amber L. Beitelshees, Rebecca A. Baillie, Arlene B. Chapman, John G. Gums, Stephen T. Turner, Eric Boerwinkle, Alison Motsinger‐Reif, Oliver Fiehn, Rhonda M. Cooper‐DeHoff, Xianlin Han, Rima Kaddurah‐Daouk, and Julie A. Johnson
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blood pressure ,lipid metabolites ,metabolomics ,pharmacogenetics ,thiazide diuretics ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
BackgroundAlthough hydrochlorothiazide (HCTZ) is a well‐established first‐line antihypertensive in the United States,
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- 2018
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12. Genetic Variants Associated With Uncontrolled Blood Pressure on Thiazide Diuretic/β‐Blocker Combination Therapy in the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) and INVEST (International Verapamil‐SR Trandolapril Study) Trials
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Oyunbileg Magvanjav, Yan Gong, Caitrin W. McDonough, Arlene B. Chapman, Stephen T. Turner, John G. Gums, Kent R. Bailey, Eric Boerwinkle, Amber L. Beitelshees, Toshihiro Tanaka, Michiaki Kubo, Carl J. Pepine, Rhonda M. Cooper‐DeHoff, and Julie A. Johnson
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combination therapy ,genomics ,pharmacogenomics ,high blood pressure ,hypertension ,β‐blockers ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
BackgroundThe majority of hypertensive individuals require combination antihypertensive therapy to achieve adequate blood pressure (BP) control. This study aimed to identify genetic variants associated with uncontrolled BP on combination therapy with a thiazide diuretic and a β‐blocker. Methods and ResultsA genome‐wide association study of uncontrolled BP on combination therapy was conducted among 314 white participants of the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) trial. Multivariable logistic regression analysis was used. Genetic variants meeting a suggestive level of significance (P
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- 2017
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13. Survey of direct patient care and payment models among pharmacy practice faculty
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Thomas C. Dowling, Aaron Thomas, and John G. Gums
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Pharmaceutical Science ,Pharmacology (medical) ,Pharmacy - Published
- 2022
14. Examination of Metoprolol Pharmacokinetics and Pharmacodynamics Across CYP2D6 Genotype‐Derived Activity Scores
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Zhichuan Li, Danxin Wang, Liang Zhao, Scott A. Mosley, Yan Gong, Rhonda M. Cooper-DeHoff, Minori Kinjo, Reginald F. Frye, Cameron D. Thomas, Taimour Y. Langaee, Arlene B. Chapman, Sarah Kim, Hyewon Kim, Larisa H. Cavallari, Issam Hamadeh, John G. Gums, David S. Estores, Siegfried Schmidt, Lanyan Fang, Julie A. Johnson, Stephan Schmidt, Nihal El Rouby, Karthik Lingineni, Kairui Feng, and Philip F. Binkley
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Adult ,Male ,medicine.medical_specialty ,CYP2D6 ,Genotype ,Administration, Oral ,Blood Pressure ,Polymorphism, Single Nucleotide ,Gastroenterology ,Article ,Pharmacokinetics ,Heart Rate ,Internal medicine ,Heart rate ,medicine ,Humans ,Pharmacology (medical) ,Prospective Studies ,Aged ,Metoprolol ,business.industry ,Research ,Significant difference ,Articles ,Middle Aged ,Adrenergic beta-1 Receptor Antagonists ,Clinical Practice ,Phenotype ,Cytochrome P-450 CYP2D6 ,Pharmacogenetics ,Modeling and Simulation ,Pharmacodynamics ,Female ,business ,medicine.drug - Abstract
Recent CYP2D6 phenotype standardization efforts by CYP2D6 activity score (AS) are based on limited pharmacokinetic (PK) and pharmacodynamic (PD) data. Using data from two independent clinical trials of metoprolol, we compared metoprolol PK and PD across CYP2D6 AS with the goal of determining whether the PK and PD data support the new phenotype classification. S‐metoprolol apparent oral clearance (CLo), adjusted for clinical factors, was correlated with CYP2D6 AS (P
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- 2020
15. Olanzapine/Samidorphan: New Drug Approved for Treating Bipolar I Disorder and Schizophrenia
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Christie Monahan, Lindsey McCoy, Jason Powell, and John G. Gums
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Adult ,Benzodiazepines ,Bipolar Disorder ,Olanzapine ,Schizophrenia ,Humans ,Pharmacology (medical) ,Naltrexone ,Antipsychotic Agents - Abstract
Objective To describe the approval of olanzapine/samidorphan, compare the clinical trial data, and summarize key findings, with a focus on impact to clinical practice. Data Sources A literature search of PubMed was performed (March 2006 to November 2021) using the following search terms: Lybalvi, olanzapine/samidorphan, olanzapine, antipsychotic, bipolar disorder, and schizophrenia. Product monographs, review articles, and randomized control trials were reviewed. Study Selection and Data Extraction Relevant English-language studies conducted in humans were considered. Primary use of Phase III clinical drug approval trials preferred; supplementary trial analysis evaluated to provide context. Data Synthesis In June 2021, the Food and Drug Administration (FDA) approved Lybalvi® (olanzapine/samidorphan) for indications including treatment of adults with schizophrenia and/or bipolar I disorder (acute manic episodes or acute episodes with mixed features) through the multi-stage ENLIGHTEN clinical trials. Participants were enrolled in 4-week, 24-week, and 52-week studies to evaluate the safety and efficacy of olanzapine/samidorphan. Subsequent secondary analysis evaluated metabolic effects. Relevance to Patient Care and Clinical Practice This review details the pharmacologic, pharmacokinetic, associated dosing and indications, and adverse effects for the drug combination olanzapine/samidorphan. Better understanding of novel drug mechanisms will help to expand on the potential role and place for use in clinical practice. Conclusion When treating complex patients with schizophrenia, the olanzapine/samidorphan combination has limited effect on medication-induced weight gain often associated with antipsychotic olanzapine monotherapy. Additional studies are needed to further define the role of olanzapine/samidorphan in bipolar I disorder and clinical practice.
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- 2022
16. Ervebo (Ebola Zaire Vaccine, Live/rVSVΔG-ZEBOV-GP): The First Licensed Vaccine for the Prevention of Ebola Virus Disease
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Chris Piszczatoski and John G. Gums
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0301 basic medicine ,Data source ,Ebola virus ,Ebola vaccine ,business.industry ,viruses ,virus diseases ,Pharmaceutical Science ,Disease ,medicine.disease_cause ,Virology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Medicine ,030212 general & internal medicine ,business - Abstract
Objective: To review the clinical data regarding the safety and efficacy of the Ervebo (Ebola Zaire vaccine, live/rVSVΔG-ZEBOV-GP) vaccine for the prevention of the Ebola virus disease. Data Sources: A literature search through PubMed, MEDLINE, and Cochrane Library was conducted for clinical trials published between January 2014 and June 2020 in the English language using the keywords Ervebo, rVSVΔG-ZEBOV, rVSVΔG-ZEBOV-GP, Ebola Zaire, and vaccine. Study Selection and Data Extraction: Articles were selected if they were related to the Food and Drug Administration (FDA) approval of Ervebo (Ebola Zaire vaccine, live/rVSVΔG-ZEBOV-GP) or provided novel data regarding this entity. Twelve articles noted in the FDA approval were chosen, along with 2 additional articles identified as providing novel information. Data Synthesis: The findings of the review show that Ervebo (Ebola Zaire vaccine, live/rVSVΔG-ZEBOV-GP) is a safe, immunogenic, and likely effective vaccine for the prevention of Ebola virus disease. Relevance to Patient Care and Clinical Practice: Ebola virus disease is highly infectious and often fatal. There have been multiple large outbreaks in the past 5 years, with no licensed treatments or vaccines. An effective vaccine could largely curtail current outbreaks and prevent further ones. Conclusion: The recent FDA approval of Ervebo (Ebola Zaire vaccine, live/rVSVΔG-ZEBOV-GP) offers the first approved vaccine for the prevention of Ebola virus disease. It has been shown to be safe, immunogenic, and likely effective for use in real-world applications for those at risk of contracting the disease.
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- 2020
17. A stepwise approach to implementing pharmacogenetic testing in the primary care setting
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Susanne B. Haga, Ebony B. Madden, Joshua C. Denny, Brian S. Decker, Kristin Weitzel, Toni I. Pollin, Aniwaa Owusu-Obeng, Eric Dietrich, John G. Gums, Barbara A. Bernhardt, Rebekah Ryanne Wu, Benjamin Q. Duong, Carol R. Horowitz, Noura S. Abul-Husn, and Meghan J. Arwood
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Pharmacology ,medicine.medical_specialty ,Primary Health Care ,business.industry ,Decision Making ,Primary care ,Precision medicine ,Pharmacogenomic Testing ,Test (assessment) ,Pharmacogenetics ,Pharmacogenomics ,Genetics ,Humans ,Molecular Medicine ,Medicine ,business ,Intensive care medicine ,Delivery of Health Care ,Special Report ,Pharmacogenetic Test ,Stepwise approach ,Patient education - Abstract
Pharmacogenetic testing can help identify primary care patients at increased risk for medication toxicity, poor response or treatment failure and inform drug therapy. While testing availability is increasing, providers are unprepared to routinely use pharmacogenetic testing for clinical decision-making. Practice-based resources are needed to overcome implementation barriers for pharmacogenetic testing in primary care.The NHGRI’s IGNITE I Network (Implementing GeNomics In pracTicE; www.ignite-genomics.org ) explored practice models, challenges and implementation barriers for clinical pharmacogenomics. Based on these experiences, we present a stepwise approach pharmacogenetic testing in primary care: patient identification; pharmacogenetic test ordering; interpretation and application of test results, and patient education. We present clinical factors to consider, test-ordering processes and resources, and provide guidance to apply test results and counsel patients. Practice-based resources such as this stepwise approach to clinical decision-making are important resources to equip primary care providers to use pharmacogenetic testing.
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- 2019
18. Metabolomics Signature of Plasma Renin Activity and Linkage with Blood Pressure Response to Beta Blockers and Thiazide Diuretics in Hypertensive European American Patients
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Caitrin W. McDonough, Lauren M. McIntyre, John G. Gums, Mai Mehanna, Julie A. Johnson, Steven M. Smith, Yan Gong, Rhonda M. Cooper-DeHoff, and Arlene B. Chapman
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hypertension ,business.industry ,plasma renin activity ,metabolomics ,blood pressure ,Endocrinology, Diabetes and Metabolism ,Pharmacology ,Atenolol ,Biochemistry ,Plasma renin activity ,Microbiology ,Article ,QR1-502 ,Hydrochlorothiazide ,Blood pressure ,Metabolomics ,Medicine ,Chlorthalidone ,business ,Molecular Biology ,Thiazide ,medicine.drug ,Metoprolol ,circulatory and respiratory physiology - Abstract
Plasma renin activity (PRA) is a predictive biomarker of blood pressure (BP) response to antihypertensives in European–American hypertensive patients. We aimed to identify the metabolic signatures of baseline PRA and the linkages with BP response to β-blockers and thiazides. Using data from the Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) trial, multivariable linear regression adjusting for age, sex and baseline systolic-BP (SBP) was performed on European–American individuals treated with metoprolol (n = 198) and chlorthalidone (n = 181), to test associations between 856 metabolites and baseline PRA. Metabolites with a false discovery rate (FDR) < 0.05 or p < 0.01 were tested for replication in 463 European–American individuals treated with atenolol or hydrochlorothiazide. Replicated metabolites were then tested for validation based on the directionality of association with BP response. Sixty-three metabolites were associated with baseline PRA, of which nine, including six lipids, were replicated. Of those replicated, two metabolites associated with higher baseline PRA were validated: caprate was associated with greater metoprolol SBP response (β = −1.7 ± 0.6, p = 0.006) and sphingosine-1-phosphate was associated with reduced hydrochlorothiazide SBP response (β = 7.6 ± 2.8, p = 0.007). These metabolites are clustered with metabolites involved in sphingolipid, phospholipid, and purine metabolic pathways. The identified metabolic signatures provide insights into the mechanisms underlying BP response.
- Published
- 2021
19. β 2 ‐Adrenergic Receptor Gene Affects the Heart Rate Response of β‐Blockers: Evidence From 3 Clinical Studies
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Daniela J. Conrado, Eric Boerwinkle, Daniel Gonzalez, Amber L. Beitelshees, Nihal El Rouby, Maximilian T. Lobmeyer, John G. Gums, Stephen T. Turner, Arlene B. Chapman, Rhonda M. Cooper-DeHoff, Mohamed H. Shahin, Julie A. Johnson, Yan Gong, and Carl J. Pepine
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Pharmacology ,medicine.medical_specialty ,Adrenergic receptor ,business.industry ,Single-nucleotide polymorphism ,Atenolol ,030226 pharmacology & pharmacy ,Clinical trial ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,030220 oncology & carcinogenesis ,Internal medicine ,Heart rate ,medicine ,Pharmacology (medical) ,business ,Pharmacogenetics ,Metoprolol ,medicine.drug ,GNB3 - Abstract
β-Blockers' heart rate (HR)-lowering effect is an important determinant of the effectiveness for this class of drugs, yet it is variable among β-blocker-treated patients. To date, genetic studies have revealed several genetic signals associated with HR response to β-blockers. However, these genetic signals have not been consistently replicated across multiple independent cohorts. Here we sought to use data from 3 hypertension clinical trials to validate single-nucleotide polymorphisms (SNPs) previously associated with the HR response to β-blockers. Using linear regression analysis, we investigated the effects of 6 SNPs in 3 genes, including ADRB1, ADRB2, and GNB3, relative to the HR response following β-blocker used in the PEAR (n = 757), PEAR-2 (n = 368), and INVEST (n = 1401) trials, adjusting for baseline HR, age, sex, and ancestry. Atenolol was used in PEAR and INVEST, and metoprolol was used in PEAR-2. We found that rs1042714 and rs1042713 in ADRB2 were significantly associated with HR response to both β-blockers in whites (rs1042714 C-allele carriers, meta-analysis β = -0.95 beats per minute [bpm], meta-analysis P = 3×10-4 ; rs1042713 A-allele carriers, meta-analysis β = -1.15 bpm, meta-analysis P = 2×10-3 ). In conclusion, the results of our analyses provide strong evidence to support the hypothesis that rs1042714 and rs1042713 in the ADRB2 gene are important predictors of HR response to cardioselective β-blockade in hypertensive patient cohorts.
- Published
- 2019
20. Plasma Renin Activity Is a Predictive Biomarker of Blood Pressure Response in European but not in African Americans With Uncomplicated Hypertension
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Julie A. Johnson, Yan Gong, John G. Gums, Zhiying Wang, Caitrin W. McDonough, Amber L. Beitelshees, Kent R. Bailey, Mai Mehanna, Gary L. Schwartz, Stephen T. Turner, Rhonda M. Cooper-DeHoff, and Arlene B. Chapman
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Original Contributions ,Clinical Decision-Making ,Urology ,Blood Pressure ,030204 cardiovascular system & hematology ,Plasma renin activity ,White People ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Hydrochlorothiazide ,Predictive Value of Tests ,Renin ,Internal Medicine ,Humans ,Medicine ,030212 general & internal medicine ,Antihypertensive Agents ,Aged ,Randomized Controlled Trials as Topic ,Metoprolol ,Receiver operating characteristic ,business.industry ,Patient Selection ,Chlorthalidone ,Middle Aged ,Atenolol ,United States ,Black or African American ,Candesartan ,Treatment Outcome ,Blood pressure ,Hypertension ,Female ,Essential Hypertension ,business ,Biomarkers ,circulatory and respiratory physiology ,medicine.drug - Abstract
BACKGROUND Interindividual variability in blood pressure (BP) response to antihypertensives has been reported. Although plasma renin activity (PRA) is a potential biomarker for personalizing antihypertensive therapy in European American (EA) and African American (AA) hypertensives, clinical utility of PRA-guided prescribing is incompletely understood. METHODS Using systematic-phased approach, PRA’s clinical utility was assessed. After categorizing by baseline PRA, clinic systolic BP (SBP) responses to metoprolol and chlorthalidone were compared in 134 EAs and 102 AAs enrolled in the Pharmacogenomics Evaluation of Antihypertensive Responses-2 (PEAR-2) trial. Receiver operating characteristic (ROC) analysis was conducted in EAs. Data from PEAR-2 AAs were used to estimate an optimal PRA cut point using multivariable linear regression models. The derived cut point in AAs was tested in a meta-analysis of 2 independent AA cohorts, and its sensitivity and specificity were assessed. RESULTS EAs with PRA < 0.65 ng/ml/hour had a greater decrease in SBP to chlorthalidone than metoprolol (by –15.9 mm Hg, adjusted P < 0.0001), whereas those with PRA ≥ 0.65 ng/ml/hour had a greater decrease in SBP to metoprolol than chlorthalidone (by 3.3 mm Hg, adjusted P = 0.04). Area under ROC curve (0.69, P = 0.0001) showed that PRA can predict SBP response among EAs. However, we observed no association between PRA and SBP response in PEAR-2 AAs. Among independent AA cohorts, those with PRA ≥ 1.3 ng/ml/hour (PEAR-2-derived cut point) responded better to atenolol/candesartan than hydrochlorothiazide (meta-analysis P = 0.01). However, sensitivity of the derived cut point was 10%. CONCLUSIONS PRA at the previously established 0.60–0.65 ng/ml/hour cut point is an effective predictive biomarker of BP response in EAs. However, we were unable to identify PRA cut point that could be used to guide antihypertensive selection in AAs. TRIAL REGISTRATION NCT01203852, NCT00246519, NCT00005520.
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- 2019
21. Targeted sequencing identifies a missense variant in the BEST3 gene associated with antihypertensive response to hydrochlorothiazide
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Yan Gong, John G. Gums, Rhonda M. Cooper-DeHoff, Steve Scherer, Mohamed H. Shahin, Taimour Y. Langaee, Julie A. Johnson, Arlene B. Chapman, Amber L. Beitelshees, Eric Boerwinkle, Stephen T. Turner, Kent R. Bailey, Sonal Singh, Caitrin W. McDonough, and Zhiying Wang
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Sodium Chloride Symporter Inhibitors ,Muscle Proteins ,Blood Pressure ,Single-nucleotide polymorphism ,030204 cardiovascular system & hematology ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,0302 clinical medicine ,Hydrochlorothiazide ,Polymorphism (computer science) ,Internal medicine ,Genetics ,medicine ,Humans ,Bestrophins ,General Pharmacology, Toxicology and Pharmaceutics ,Molecular Biology ,Antihypertensive Agents ,Genetic Association Studies ,Genetics (clinical) ,Thiazide ,Genetic association ,business.industry ,Angiotensin II ,Odds ratio ,Middle Aged ,030104 developmental biology ,Endocrinology ,Atenolol ,Genetic epidemiology ,Hypertension ,Molecular Medicine ,Female ,business ,medicine.drug - Abstract
Chromosome 12q15 was identified in Genetic Epidemiology of Response Assessment (GERA) and replicated in Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) for its association with blood pressure (BP) response to hydrochlorothiazide (HCTZ). However, the functional variant is unknown and we aimed to identify the likely functional variants through targeted sequencing. The chromosome 12q15 region was sequenced in 397 best and worst responders to HCTZ in PEAR (N=199) and GERA (N=198) hypertensive study participants. Logistic regression was used for the association analysis adjusting for age, sex, race, and principal components 1 and 2. For validation, the significant single nucleotide polymorphism was tested for association with the change in systolic (ΔSBP) and diastolic BP (ΔDBP) post-treatment in the entire PEAR (N=370) and GERA (N=570) cohorts. A novel missense polymorphism (G>A, Pro383Leu) in BEST3, rs61747221, was significantly associated with better HCTZ response (P=0.0021, odds ratio=2.05). It was validated in the entire cohort of PEAR (ΔSBP: P=0.021, β=-1.60, ΔDBP: P=0.023, β=-1.08) and GERA (ΔSBP: P=0.028, β=-1.95, ΔDBP: P=0.032, β=-1.28). BEST3 encodes the calcium sensitive chloride channel in the vascular smooth muscle implicated in the regulation of BP, especially in response to vasoconstrictors like angiotensin II. These results suggest that BEST3 is involved in the chronic BP lowering mechanism of thiazides and highlight its importance as a genetic predictor of the BP response to thiazide diuretics.
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- 2018
22. Race-Specific Comparisons of Antihypertensive and Metabolic Effects of Hydrochlorothiazide and Chlorthalidone
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Arlene B. Chapman, John G. Gums, Rhonda M. Cooper-DeHoff, Julie A. Johnson, and Lakshmi Manasa Chekka
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Adult ,Male ,medicine.medical_specialty ,030204 cardiovascular system & hematology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Hydrochlorothiazide ,Metabolic Diseases ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Prospective Studies ,Adverse effect ,Thiazide ,Antihypertensive Agents ,business.industry ,Chlorthalidone ,General Medicine ,Middle Aged ,Race Factors ,Clinical trial ,Blood pressure ,Metabolic effects ,Hypertension ,Multivariate Analysis ,Cardiology ,Female ,Blood pressure lowering ,business ,medicine.drug - Abstract
BACKGROUND: Chlorthalidone is recommended over hydrochlorothiazide (HCTZ) as the preferred thiazide, but the supporting evidence is not robust at routinely used doses, or in whites versus blacks, in whom differences in response to thiazides are well known. We compare the efficacy and safety of HCTZ and chlorthalidone as first-line therapies for white and black hypertensive patients. METHODS: We compared treatment related outcomes between the HCTZ arm (12.5mg for 2–3 weeks; 25mg for additional 6 weeks) of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR, n=376) and chlorthalidone arm (15mg for 2 weeks; 25mg for additional 6 weeks) of PEAR-2 (n=326) clinical trials, in 17–65 year-old mild-moderate uncomplicated hypertensive whites and blacks. RESULTS: Mean systolic/diastolic blood pressure (SBP/DBP) reduction with HCTZ vs chlorthalidone: 8±8/4±5 vs 12±9/7±5 mmHg in whites (p
- Published
- 2020
23. Abstract 15986: Plasma Microrna Profiling Reveals Potential Biomarkers of Thiazide Response
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Renne Rolf, Stephen T. Turner, John G. Gums, Taimour Y. Langaee, Lakshmi Manasa Chekka, Julie A. Johnson, Danxin Wang, Rhonda M. Cooper-DeHoff, and Arlene B. Chapman
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business.industry ,Physiology (medical) ,Potential biomarkers ,medicine ,Cancer research ,Cardiology and Cardiovascular Medicine ,Microrna profiling ,business ,Thiazide ,medicine.drug - Abstract
Introduction: Thiazide diuretics (TZDs) are the second most frequently prescribed class of antihypertensives. But Hypothesis: Plasma miRNAs may play a role in TZD response; we aim to identify those associated with hydrochlorothiazide (HCTZ) response. Methods: We profiled 754 miRNAs in baseline (untreated) plasma samples of 36 uncomplicated hypertensive adults (18 Responders (R) and 18 Non-responders (NR) based on their diastolic BP (DBP) response to HCTZ therapy) from the Pharmacogenomic Evaluation of Antihypertensive Responses clinical trial, using the real-time qPCR based TaqMan OpenArray Human microRNA panel. We filtered out miRNAs with low amplification scores and Cq>38 and samples with low miRNA expression. Combination of miR-223 and miR-19b (identified as most stably expressed miRNAs by NormFinder Software) was used to normalize expression across samples. We used MannWhitney U test to identify microRNAs differentially expressed between R and NR; linear and logistic regressions for associations of miRNA expression with BP response. FDA corrected p Results: Mean systolic BP (SBP)/DBP change in R was 14/10 mmHg and in NR 0/1 mmHg. We found 77 miRNAs to be consistently expressed across samples, of which 11 were upregulated and 14 downregulated with >2-fold difference between R and NR. Though no miRNAs reached FDR p Conclusions: In this first ever genome-wide miRNA study of antihypertensive drug response, we discovered circulating miRNAs associated with BP response to HCTZ. Future studies are planned to validate these findings in a larger cohort, across different race group and across different TZD.
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- 2020
24. Design and Early Implementation Successes and Challenges of a Pharmacogenetics Consult Clinic
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D. Max Smith, Benjamin Q. Duong, Amanda L. Elchynski, Ying Nagoshi, Kristin Wiisanen, Ashleigh Wright, John G. Gums, Kelsey J. Cook, Amanda R. Elsey, Larisa H. Cavallari, Jeffrey Budd, Neal Holland, Julie A. Johnson, Eric I. Rosenberg, Eric Dietrich, Meghan J. Arwood, Edlira Maska, Katherine Huber, and Danielle Panna
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precision medicine ,pharmacogenetics ,pharmacogenomics ,implementation ,primary care ,internal medicine ,CYP2C19 ,CYP2D6 ,medicine.medical_specialty ,Referral ,health care facilities, manpower, and services ,education ,Pharmacist ,lcsh:Medicine ,Primary care ,030226 pharmacology & pharmacy ,Article ,03 medical and health sciences ,0302 clinical medicine ,health services administration ,medicine ,Reimbursement ,health care economics and organizations ,business.industry ,lcsh:R ,General Medicine ,Precision medicine ,Early results ,030220 oncology & carcinogenesis ,Pharmacogenomics ,Family medicine ,business ,Pharmacogenetics - Abstract
Pharmacogenetic testing (PGT) is increasingly being used as a tool to guide clinical decisions. This article describes the development of an outpatient, pharmacist-led, pharmacogenetics consult clinic within internal medicine, its workflow, and early results, along with successes and challenges. A pharmacogenetics-trained pharmacist encouraged primary care physicians (PCPs) to refer patients who were experiencing side effects/ineffectiveness from certain antidepressants, opioids, and/or proton pump inhibitors. In clinic, the pharmacist confirmed the need for and ordered CYP2C19 and/or CYP2D6 testing, provided evidence-based pharmacogenetic recommendations to PCPs, and educated PCPs and patients on the results. Operational and clinical metrics were analyzed. In two years, 91 referred patients were seen in clinic (mean age 57, 67% women, 91% European-American). Of patients who received PGT, 77% had at least one CYP2C19 and/or CYP2D6 phenotype that would make conventional prescribing unfavorable. Recommendations suggested that physicians change a medication/dose for 59% of patients; excluding two patients lost to follow-up, 87% of recommendations were accepted. Challenges included PGT reimbursement and referral maintenance. High frequency of actionable results suggests physician education on who to refer was successful and illustrates the potential to reduce trial-and-error prescribing. High recommendation acceptance rate demonstrates the pharmacist’s effectiveness in providing genotype-guided recommendations, emphasizing a successful pharmacist–physician collaboration.
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- 2020
25. Sorting nexin 1 loss results in increased oxidative stress and hypertension
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John G. Gums, Chunyu Zeng, Van Anthony M. Villar, Xiaoyan Wang, Gary L. Schwartz, Jian Yang, Eric Boerwinkle, Julie A. Johnson, Rhonda M. Cooper-DeHoff, Jun B. Feranil, Edward J. Weinman, Robin A. Felder, Ines Armando, Arlene B. Chapman, Santiago Cuevas, John E. Jones, Amber L. Beitelshees, Stephen T. Turner, Pedro A. Jose, and Laureano D. Asico
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0301 basic medicine ,Male ,medicine.medical_specialty ,Blood Pressure ,medicine.disease_cause ,Kidney ,Biochemistry ,Article ,Receptor, Angiotensin, Type 1 ,Cell Line ,Kidney Tubules, Proximal ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Internal medicine ,Genetics ,medicine ,Animals ,Humans ,RNA, Small Interfering ,Receptor ,Molecular Biology ,Sorting Nexins ,chemistry.chemical_classification ,Reactive oxygen species ,Angiotensin II receptor type 1 ,NADPH oxidase ,biology ,NADPH Oxidases ,Angiotensin II ,Oxidative Stress ,Protein Transport ,030104 developmental biology ,Blood pressure ,Endocrinology ,chemistry ,Apocynin ,Hypertension ,biology.protein ,Female ,Reactive Oxygen Species ,Oxidation-Reduction ,030217 neurology & neurosurgery ,Oxidative stress ,Biotechnology - Abstract
Acute renal depletion of sorting nexin 1 (SNX1) in mice results in blunted natriuretic response and hypertension due to impaired dopamine D(5) receptor (D(5)R) activity. We elucidated the molecular mechanisms for these phenotypes in Snx1(−/−) mice. These mice had increased renal expressions of angiotensin II type 1 receptor (AT(1)R), NADPH oxidase (NOX) subunits, D(5)R, and NaCl cotransporter. Basal reactive oxygen species (ROS), NOX activity, and blood pressure (BP) were also higher in Snx1(−/−) mice, which were normalized by apocynin, a drug that prevents NOX assembly. Renal proximal tubule (RPT) cells from hypertensive (HT) Euro-American males had deficient SNX1 activity, impaired D(5)R endocytosis, and increased ROS compared with cells from normotensive (NT) Euro-American males. siRNA-mediated depletion of SNX1 in RPT cells from NT subjects led to a blunting of D(5)R agonist-induced increase in cAMP production and decrease in Na(+) transport, effects that were normalized by over-expression of SNX1. Among HT African-Americans, three of the 12 single nucleotide polymorphisms interrogated for the SNX1 gene were associated with a decrease in systolic BP in response to hydrochlorothiazide (HCTZ). The results illustrate a new paradigm for the development of hypertension and imply that the trafficking protein SNX1 may be a crucial determinant for hypertension and response to antihypertensive therapy.
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- 2020
26. Genome Wide Analysis Approach Suggests Chromosome 2 Locus to be Associated with Thiazide and Thiazide Like-Diuretics Blood Pressure Response
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Yan Gong, John G. Gums, Kent R. Bailey, Arlene B. Chapman, Eric Boerwinkle, Rhonda M. Cooper-DeHoff, Caitrin W. McDonough, Sonal Singh, Stephen T. Turner, and Julie A. Johnson
- Subjects
Adult ,Male ,0301 basic medicine ,Pharmacogenomic Variants ,lcsh:Medicine ,Blood Pressure ,Single-nucleotide polymorphism ,030204 cardiovascular system & hematology ,Bioinformatics ,Genome-wide association studies ,Polymorphism, Single Nucleotide ,Article ,White People ,03 medical and health sciences ,0302 clinical medicine ,Hydrochlorothiazide ,medicine ,Humans ,SNP ,Prospective Studies ,lcsh:Science ,Diuretics ,Thiazide ,Multidisciplinary ,business.industry ,lcsh:R ,Chlorthalidone ,Middle Aged ,Pharmacogenomic Testing ,3. Good health ,Black or African American ,Calcineurin ,Calcineurin complex ,030104 developmental biology ,Genetic Loci ,Chromosomes, Human, Pair 2 ,Pharmacogenomics ,Hypertension ,lcsh:Q ,Female ,business ,Genome-Wide Association Study ,medicine.drug - Abstract
Chlorthalidone (CTD) is more potent than hydrochlorothiazide (HCTZ) in reducing blood pressure (BP) in hypertensive patients, though both are plagued with BP response variability. However, there is a void in the literature regarding the genetic determinants contributing to the variability observed in BP response to CTD. We performed a discovery genome wide association analysis of BP response post CTD treatment in African Americans (AA) and European Americans (EA) from the Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) study and replication in an independent cohort of AA and EA treated with HCTZ from the PEAR study, followed by a race specific meta-analysis of the two studies. Successfully replicated SNPs were further validated in beta-blocker treated participants from PEAR-2 and PEAR for opposite direction of association. The replicated and validated signals were further evaluated by protein-protein interaction network analysis. An intronic SNP rs79237970 in the WDR92 (eQTL for PPP3R1) was significantly associated with better DBP response to CTD (p = 5.76 × 10−6, β = −15.75) in the AA cohort. This SNP further replicated in PEAR (p = 0.00046, β = −9.815) with a genome wide significant meta-analysis p-value of 8.49 × 10−9. This variant was further validated for opposite association in two β-blockers treated cohorts from PEAR-2 metoprolol (p = 9.9 × 10−3, β = 7.47) and PEAR atenolol (p = 0.04, β = 4.36) for association with DBP. Studies have implicated WDR92 in coronary artery damage. PPP3R1 is the regulatory subunit of the calcineurin complex. Use of calcineurin inhibitors is associated with HTN. Studies have also shown polymorphisms in PPP3R1 to be associated with ventricular hypertrophy in AA hypertensive patients. Protein-protein interaction analysis further identified important hypertension related pathways such as inositol phosphate-mediated signaling and calcineurin-NFAT signaling cascade as important biological process associated with PPP3R1 which further strengthen the potential importance of this signal. These data collectively suggest that WDR92 and PPP3R1 are novel candidates that may help explain the genetic underpinnings of BP response of thiazide and thiazide-like diuretics and help identify the patients better suited for thiazide and thiazide-like diuretics compared to β-blockers for improved BP management. This may further help advance personalized approaches to antihypertensive therapy.
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- 2019
27. Andexanet alfa for reversal of factor Xa inhibitor-associated anticoagulation
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Elise Carpenter, Divita Singh, Eric Dietrich, and John G. Gums
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medicine.drug_mechanism_of_action ,Factor Xa Inhibitor ,apixaban ,Review ,030204 cardiovascular system & hematology ,Pharmacology ,Eliquis ,Savaysa ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Lovenox ,Pharmacology (medical) ,030212 general & internal medicine ,betrixaban ,rivaroxaban ,business.industry ,lcsh:RM1-950 ,virus diseases ,enoxaparin ,Bevyxxa ,Xarelto ,andexanet alfa ,lcsh:Therapeutics. Pharmacology ,edoxaban ,reversal ,business ,antidote ,Andexanet alfa ,medicine.drug - Abstract
Background: Review of clinical data on andexanet alfa for the reversal of factor Xa (FXa) inhibitor associated anticoagulation. Data sources: In the present review, we identified articles via PubMed using the combined keywords andexanet alfa, apixaban, enoxaparin, edoxaban, and rivaroxaban. Additional online searches via PubMed, Google Scholar, and Lexicomp were conducted for both prescribing and cost information. Portola Pharmaceuticals was contacted for information used for United States Food and Drug Administration approval of andexanet alfa. Study selection and data extraction: English-language clinical trials and reviews published between January 2008 and April 2019 were included for review. Bibliographies of selected articles were reviewed manually for relevant publications, focusing on reversal strategies for apixaban, enoxaparin, edoxaban, or rivaroxaban associated anticoagulation using andexanet alfa. Review articles were excluded. Data synthesis: The safety and tolerability of andexanet alfa were evaluated in one phase I, two phase II, and one phase III clinical trials. The use of andexanet alfa for reversing FXa inhibitor-associated anticoagulation were evaluated in the phase III ANNEXA-4 study. Conclusions: Studies evaluating laboratory parameters for coagulation show that andexanet alfa rapidly neutralizes the anticoagulant effects of apixaban, enoxaparin, edoxaban, and rivaroxaban. Clinical studies show that andexanet alfa improves markers related to coagulation, and reverses major bleeding in healthy volunteers and patients with life-threatening bleeding. Interruption of anticoagulation may result in thromboembolic and ischemic events. The use of andexanet alfa requires close monitoring for signs and symptoms of thromboembolic events, ischemic events, and cardiac arrest. Furthermore, anticoagulation should be resumed following the administration of andexanet alfa as soon as medically appropriate.
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- 2019
28. Evaluation of SAMe-TT2R2 Score on Predicting Success With Extended-Interval Warfarin Monitoring
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Eric Dietrich, Nicholas W. Carris, John G. Gums, Steven M. Smith, and Andrew Y. Hwang
- Subjects
medicine.medical_specialty ,business.industry ,medicine.drug_class ,Warfarin ,030204 cardiovascular system & hematology ,Vitamin K antagonist ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Warfarin monitoring ,Post-hoc analysis ,Medicine ,Pharmacology (medical) ,Medical history ,In patient ,030212 general & internal medicine ,Limited evidence ,business ,Patient factors ,medicine.drug - Abstract
Background: In patients with stable international normalized ratios, 12-week extended-interval warfarin monitoring can be considered; however, predictors of success with this strategy are unknown. The previously validated SAMe-TT2R2 score (considering sex, age, medical history, treatment, tobacco, and race) predicts anticoagulation control during standard follow-up (every 4 weeks), with lower scores associated with greater time in therapeutic range. Objective: To evaluate the ability of the SAMe-TT2R2 score in predicting success with extended-interval warfarin follow-up in patients with previously stable warfarin doses. Methods: In this post hoc analysis of a single-arm feasibility study, baseline SAMe-TT2R2 scores were calculated for patients with ≥1 extended-interval follow-up visit. The primary analysis assessed achieved weeks of extended-interval follow-up according to baseline SAMe-TT2R2 scores. Results: A total of 47 patients receiving chronic anticoagulation completed a median of 36 weeks of extended-interval follow-up. The median baseline SAMe-TT2R2 score was 1 (range 0-5). Lower SAMe-TT2R2 scores appeared to be associated with greater duration of extended-interval follow-up achieved, though the differences between scores were not statistically significant. No individual variable of the SAMe-TT2R2 score was associated with achieved weeks of extended-interval follow-up. Analysis of additional patient factors found that longer duration (≥24 weeks) of prior stable treatment was significantly associated with greater weeks of extended-interval follow-up completed ( P = 0.04). Conclusion and Relevance: This pilot study provides limited evidence that the SAMe-TT2R2 score predicts success with extended-interval warfarin follow-up but requires confirmation in a larger study. Further research is also necessary to establish additional predictors of successful extended-interval warfarin follow-up.
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- 2018
29. Blood pressure response to metoprolol and chlorthalidone in European and African Americans with hypertension
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Stephen T. Turner, Amber L. Beitelshees, Julie A. Johnson, Mai Mehanna, Arlene B. Chapman, Yan Gong, Rhonda M. Cooper-DeHoff, Gary L. Schwartz, Caitrin W. McDonough, and John G. Gums
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African american ,medicine.medical_specialty ,business.industry ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Diastole ,030204 cardiovascular system & hematology ,Sequential treatment ,03 medical and health sciences ,0302 clinical medicine ,Blood pressure ,Internal medicine ,Pharmacogenomics ,Internal Medicine ,Cardiology ,Medicine ,Chlorthalidone ,030212 general & internal medicine ,Cardiology and Cardiovascular Medicine ,business ,Antihypertensive drug ,medicine.drug ,Metoprolol - Abstract
Despite the availability of many antihypertensive drug classes, half of patients with hypertension have uncontrolled blood pressure (BP). The authors sought to assess the effect of age on BP response in European American and African American patients with hypertension. Clinic BP from the PEAR2 (Pharmacogenomics Evaluation of Antihypertensive Responses 2) study was used to estimate BP responses from baseline following sequential treatment with metoprolol 100 mg twice daily and chlorthalidone 25 mg daily for 8 to 9 weeks each, with a minimum 4-week washout between treatments. BP responses to both drugs were compared in 159 European Americans and 119 African Americans by age with adjustment for baseline BP and sex. European Americans younger than 50 years responded better to metoprolol than chlorthalidone (diastolic BP: -9.6 ± 8.0 vs -5.9 ± 6.8 mm Hg, adjusted P = .003), whereas patients 50 years and older responded better to chlorthalidone than metoprolol (systolic BP: -18.7 ± 13.8 vs -13.6 ± 14.8 mm Hg, adjusted P = .008). African Americans younger than 50 years responded similarly to both drugs, whereas those 50 years and older responded better to chlorthalidone than metoprolol (-17.0 ± 13.2/-9.6 ± 7.5 vs -7.0 ± 18.6/-6.7 ± 9.3 mm Hg, adjusted P
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- 2017
30. Erenumab: A First-in-Class Monoclonal Antibody for Migraine Prevention
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Scott Garland, John G. Gums, and Steven M. Smith
- Subjects
Adult ,Male ,medicine.medical_specialty ,Migraine Disorders ,MEDLINE ,Calcitonin gene-related peptide ,Placebo ,Antibodies, Monoclonal, Humanized ,03 medical and health sciences ,0302 clinical medicine ,Chronic Migraine ,Calcitonin Gene-Related Peptide Receptor Antagonists ,Internal medicine ,Medicine ,Prevention of migraines ,Humans ,Pharmacology (medical) ,030212 general & internal medicine ,Adverse effect ,business.industry ,Antibodies, Monoclonal ,Middle Aged ,medicine.disease ,Clinical trial ,Migraine ,Female ,business ,030217 neurology & neurosurgery - Abstract
Objective: To review the pharmacology, efficacy, and safety of the calcitonin gene-related peptide (CGRP) inhibitor erenumab for migraine preventive therapy. Data Sources: A MEDLINE/PubMed search (January 2000 to January 2019) was conducted using the keywords erenumab-aooe, erenumab, migraine, migraine prophylaxis, migraine prevention, and chronic migraine. Additional articles were identified by hand from references. Study Selection and Data Extraction: We included English-language articles (excluding poster presentations) evaluating erenumab pharmacology, efficacy, or safety in humans for migraine prevention. Data Synthesis: Erenumab is a CGRP inhibitor that inhibits vasodilation in response to acute migraines, which decreases pain perception during the migraine. Erenumab efficacy and safety has only been compared with placebo, but its reduction in monthly migraine days (MMDs) and medication response (≥50% reduction in MMDs) are comparable to current recommended off-label therapies for migraine prevention in short-term treatment studies. Additionally, erenumab is associated with low adverse event burden with no difference found compared with placebo per published clinical trials. Relevance to Patient Care and Clinical Practice: Erenumab is the first medication approved in the United States for the prevention of migraines in adults. No head-to-head data are available, but existing data suggest that erenumab is at least as effective as current off-label products and with reduced adverse effects. Conclusion: Erenumab is an effective once-monthly injectable agent for migraine prevention in patients with chronic or episodic migraine. It is also effective for patients who have previously failed migraine preventive therapy. Erenumab has a favorable adverse effect profile, which may improve patient adherence.
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- 2019
31. β
- Author
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Mohamed H, Shahin, Nihal El, Rouby, Daniela J, Conrado, Daniel, Gonzalez, Yan, Gong, Maximilian T, Lobmeyer, Amber L, Beitelshees, Eric, Boerwinkle, John G, Gums, Arlene, Chapman, Stephen T, Turner, Carl J, Pepine, Rhonda M, Cooper-DeHoff, and Julie A, Johnson
- Subjects
Male ,Genotype ,Adrenergic beta-Antagonists ,Black People ,Middle Aged ,Heterotrimeric GTP-Binding Proteins ,Polymorphism, Single Nucleotide ,White People ,Article ,Atenolol ,Heart Rate ,Hypertension ,Humans ,Female ,Receptors, Adrenergic, beta-2 ,Receptors, Adrenergic, beta-1 ,Alleles ,Metoprolol - Abstract
β-Blockers’ heart rate (HR)-lowering effect is an important determinant of the effectiveness for this class of drugs, yet it is variable among β-blocker–treated patients. To date, genetic studies have revealed several genetic signals associated with HR response to β-blockers. However, these genetic signals have not been consistently replicated across multiple independent cohorts. Here we sought to use data from 3 hypertension clinical trials to validate single-nucleotide polymorphisms (SNPs) previously associated with the HR response to β-blockers. Using linear regression analysis, we investigated the effects of 6 SNPs in 3 genes, including ADRB1, ADRB2, and GNB3, relative to the HR response following β-blocker used in the PEAR (n = 757), PEAR-2 (n = 368), and INVEST (n = 1401) trials, adjusting for baseline HR, age, sex, and ancestry. Atenolol was used in PEAR and INVEST, and metoprolol was used in PEAR-2. We found that rs1042714 and rs1042713 in ADRB2 were significantly associated with HR response to both β-blockers in whites (rs1042714 C-allele carriers, meta-analysis β = −0.95 beats per minute [bpm], meta-analysis P = 3×10(−4); rs1042713 A-allele carriers, meta-analysis β = −1.15 bpm, meta-analysis P = 2×10(−3)). In conclusion,the results of our analyses provide strong evidence to support the hypothesis that rs1042714 and rs1042713 in the ADRB2 gene are important predictors of HR response to cardioselective β-blockade in hypertensive patient cohorts.
- Published
- 2019
32. Effect of plasma MicroRNA on antihypertensive response to beta blockers in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) studies
- Author
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Rhonda M. Cooper-DeHoff, Julie A. Johnson, John G. Gums, Lamia El-Wakeel, Arlene B. Chapman, Mohamed Hassan M. Solayman, Manal El-Hamamsy, Amber L. Beitelshees, Yan Gong, Taimour Y. Langaee, Stephen T. Turner, Mohamed H. Shahin, Eric Boerwinkle, and Osama A. Badary
- Subjects
Adult ,Male ,medicine.drug_class ,Adrenergic beta-Antagonists ,Pharmaceutical Science ,02 engineering and technology ,Pharmacology ,030226 pharmacology & pharmacy ,Article ,03 medical and health sciences ,0302 clinical medicine ,microRNA ,medicine ,Humans ,Receptor ,Beta blocker ,Antihypertensive Agents ,Metoprolol ,PEAR ,business.industry ,Middle Aged ,021001 nanoscience & nanotechnology ,Atenolol ,MicroRNAs ,Pharmacogenomics ,Hypertension ,Biomarker (medicine) ,Female ,0210 nano-technology ,business ,medicine.drug - Abstract
β-blockers show variable efficacy as antihypertensives. Herein, we evaluated plasma miRNAs as biomarkers for defining antihypertensive response to β-blockers. Expression of 22 β-blocker pharmacodynamics-related miRNAs was assessed in baseline plasma samples from 30 responders and 30 non-responders to metoprolol from the PEAR-2 study (Discovery). Logistic regression was performed to identify miRNAs significantly associated with metoprolol response. Those miRNAs were profiled in baseline plasma samples from 25 responders and 25 non-responders to atenolol from the PEAR study (validation). In discovery, miR-101, miR-27a, miR-22, miR-19a, and let-7e were significantly associated with metoprolol response (P = 0.01, 0.017, 0.025, 0.025, and 0.04, respectively). In validation, miR-19a was significantly associated with atenolol response (P = 0.038). Meta-analysis between PEAR-2 and PEAR revealed significant association between miR-19a (P = 0.004), miR-101 (P = 0.006), and let-7e (P = 0.012) and β-blocker response. Hence, miR-19a, miR-101, and let-7e, which regulate β1-adrenergic receptor and other β-blocker pharmacodynamics-related genes, may be biomarkers for antihypertensive response to β-blockers.
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- 2019
33. Genomic Association Analysis Reveals Variants Associated With Blood Pressure Response to Beta-Blockers in European Americans
- Author
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Julie A. Johnson, Nihal El Rouby, Stephen T. Turner, John G. Gums, Eric Boerwinkle, Caitrin W. McDonough, Yan Gong, Arlene B. Chapman, Sonal Singh, Rhonda M. Cooper-DeHoff, and Kent R. Bailey
- Subjects
Male ,030213 general clinical medicine ,Candidate gene ,Adrenergic beta-Antagonists ,Single-nucleotide polymorphism ,Blood Pressure ,Biology ,030226 pharmacology & pharmacy ,General Biochemistry, Genetics and Molecular Biology ,Linkage Disequilibrium ,White People ,Article ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Meta-Analysis as Topic ,Diastole ,medicine ,Humans ,General Pharmacology, Toxicology and Pharmaceutics ,Gene ,Genetic association ,Genetics ,General Neuroscience ,lcsh:Public aspects of medicine ,Research ,lcsh:RM1-950 ,Reproducibility of Results ,lcsh:RA1-1270 ,General Medicine ,Articles ,Middle Aged ,Atenolol ,Solute carrier family ,lcsh:Therapeutics. Pharmacology ,Pharmacogenomics ,Expression quantitative trait loci ,Female ,medicine.drug ,Genome-Wide Association Study ,Metoprolol - Abstract
European Americans (EA) have a better antihypertensive response to β-blockers when compared with African Americans, albeit with some variability. We undertook a genomewide association study to elucidate the underlying genetic determinants in EA contributing to this variability in blood pressure (BP) response. A discovery genomewide association study of change in BP post-metoprolol treatment was performed in EA participants (n = 201) from the Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) study and tested for replication in the atenolol-treated EA from the PEAR study (n = 233). Rs294610 in the FGD5, which encodes for FYVE, RhoGEF and PH Domain Containing 5, (expression quantitative trait loci for FGD5 in the small intestine) was significantly associated with increased diastolic BP response to β-blockers in the PEAR-2 study (P = 3.41 × 10-6 , β = -2.70) and replicated (P = 0.01, β = -1.17) in the PEAR study. Post-meta-analysis of these studies, an additional single nucleotide polymorphism rs45545233 in the SLC4A1, encoding for Solute Carrier Family 4 Member 1, (expression quantitative trait loci for dual specificity phosphatase 3 in the artery tibial) was identified that was significantly associated with a poor response to β-blockers (P = 3.43 × 10-6 , β = 4.57) and was replicated in the atenolol add-on cohort (P = 0.007, β = 4.97). We identified variants in FGD5 and SLC4A1, which have been previously cited as candidate genes for hypertension, to be associated with a β-blocker BP response in EA. Further elucidation is warranted of the underlying mechanisms of these variants and genes by which they influence the BP response to β-blockers.
- Published
- 2019
34. Incident-to Billing for Pharmacists
- Author
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John G. Gums and Eric Dietrich
- Subjects
Patient Care Team ,medicine.medical_specialty ,business.industry ,Delivery of Health Care, Integrated ,Salaries and Fringe Benefits ,health care facilities, manpower, and services ,Health Policy ,education ,Pharmaceutical Science ,Pharmacy ,Health outcomes ,Pharmacists ,030226 pharmacology & pharmacy ,03 medical and health sciences ,0302 clinical medicine ,health services administration ,Family medicine ,Pharmaceutical Services ,medicine ,Ambulatory Care ,Humans ,030212 general & internal medicine ,business ,Inclusion (education) ,health care economics and organizations - Abstract
The inclusion of pharmacists on care teams has been shown to improve clinical and economic health outcomes. However, a significant barrier to the widespread incorporation of pharmacists into care teams is the ability to financially support the salary of the pharmacist. A mechanism to improve the ability of pharmacists to generate clinical revenue already exists in the form of incident-to billing, although there remains considerable uncertainty regarding the criteria for incident-to billing and specifically how pharmacists can use this model to capture revenue for clinical services. In this article, we discuss incident-to billing criteria as it pertains to outpatient clinics, common misconceptions related to incident-to billing, and how clinical pharmacists may use this mechanism to generate revenue for the clinical services they provide. DISCLOSURES: This work was not supported by any funding source. The authors have no relevant conflicts of interest to disclose.
- Published
- 2018
35. The Adaptation of a Clinic-Adjacent Parking Garage for Drive-In COVID-19 Vaccination
- Author
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Laura Gruber, Yushi Huang, Natasha Patel, John G. Gums, Tracy Green, Lindsay Swilley, Rachel Reise, Silken A Usmani, and Marvin A. Dewar
- Subjects
Medicine (General) ,medicine.medical_specialty ,Operationalization ,Coronavirus disease 2019 (COVID-19) ,SARS-CoV-2 ,business.industry ,Health Policy ,Public health ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Public Health, Environmental and Occupational Health ,drive-in vaccinations ,medicine.disease ,COVID-19 vaccinations ,Vaccination ,R5-920 ,medicine ,Outpatient clinic ,Medical emergency ,Public aspects of medicine ,RA1-1270 ,business ,Adaptation (computer science) ,Practical implications ,Original Research - Abstract
Purpose: The distribution and vaccination of COVID-19 vaccines to billions of people worldwide will likely be one of the biggest public health undertakings in history. There has been a large focus on identifying processes to safely, efficiently, and effectively vaccinate large populations. We aimed to describe the development and operationalization of a drive-in COVID-19 vaccine site in a parking garage adjacent to outpatient clinics at University of Florida (UF) Health Physicians and how it was informed by the roll-out of SARS-CoV-2 testing and administration of respiratory vaccinations. Design/Methodology/Approach: A technical description and analysis of a drive-in COVID-19 vaccine site. Findings: We incrementally increased the number of vaccines performed per day from 300 in the first 2 weeks to 700 an additional 2 weeks later. By the end of January, we completed nearly 14 000 vaccinations. At this capacity, we estimate the site could performed 5000 vaccinations per week. Practical Implications: This manuscript provides step-by-step guidance how to develop, operationalize, and implement a sustainable drive-in COVID-19 vaccination site. Originality/Value: To our knowledge, this is the first description of a drive-in approach to COVID-19 vaccination. Our findings can help inform other health entities as they develop or expand vaccination efforts that may serve as a template for other sites to adapt.
- Published
- 2021
36. Comparison of Blood Pressure Control Rates Among Recommended Drug Selection Strategies for Initial Therapy of Hypertension
- Author
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Abdurrahman M. Hamadah, Kent R. Bailey, John G. Gums, Gary L. Schwartz, Rhonda M. Cooper-DeHoff, Julie A. Johnson, Arlene B. Chapman, Kamel A. Gharaibeh, and Stephen T. Turner
- Subjects
Adult ,Male ,medicine.medical_specialty ,medicine.drug_class ,Blood Pressure ,030204 cardiovascular system & hematology ,Pharmacology ,Plasma renin activity ,White People ,03 medical and health sciences ,0302 clinical medicine ,Hydrochlorothiazide ,Internal medicine ,Renin ,Internal Medicine ,medicine ,Humans ,030212 general & internal medicine ,Antihypertensive drug ,Beta blocker ,Antihypertensive Agents ,Thiazide ,Retrospective Studies ,business.industry ,Age Factors ,Middle Aged ,Atenolol ,Black or African American ,Blood pressure ,Hypertension ,Ambulatory ,Original Article ,Female ,business ,medicine.drug - Abstract
BACKGROUND Several approaches to initiation of antihypertensive therapy have been suggested. These include thiazide diuretics (TDs) as the first drug in all patients, initial drug selection based on age and race criteria, or therapy selection based on measures of plasma renin activity (PRA). It is uncertain which of these strategies achieves the highest control rate with monotherapy in Stage-I hypertension. We sought to compare control rates among these strategies. METHODS We used data from the Pharmacogenomic Evaluation of Antihypertensive Responses study (PEAR) to estimate control rates for each strategy: (i) TD for all, (ii) age- and race-based strategy: Hydrochlorothiazide (HCTZ) for all blacks and for whites ≥50 years and a renin-angiotensin system inhibitor (atenolol) for whites
- Published
- 2016
37. Melatonin Pathway and Atenolol‐Related Glucose Dysregulation: Is There a Correlation?
- Author
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Arlene B. Chapman, Taimour Y. Langaee, Rhonda M. Cooper-DeHoff, Amber L. Beitelshees, Shin Wen Chang, John G. Gums, Caitrin W. McDonough, Julie A. Johnson, N Nasiri Kenari, Stephen T. Turner, and Yan Gong
- Subjects
0301 basic medicine ,Blood Glucose ,Male ,Candidate gene ,medicine.medical_specialty ,Single-nucleotide polymorphism ,Carbohydrate metabolism ,Biology ,Melatonin receptor ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Article ,White People ,Melatonin ,03 medical and health sciences ,chemistry.chemical_compound ,Internal medicine ,Protein Kinase C beta ,medicine ,Humans ,General Pharmacology, Toxicology and Pharmaceutics ,Creatinine ,General Neuroscience ,Research ,General Medicine ,Articles ,Fasting ,Middle Aged ,Atenolol ,030104 developmental biology ,Endocrinology ,Glucose ,chemistry ,Female ,sense organs ,Pharmacogenetics ,medicine.drug ,Signal Transduction - Abstract
Lower melatonin level, melatonin receptor gene variations, and atenolol treatment are associated with glucose dysregulation. We investigated whether atenolol-related glucose and melatonin changes are correlated, and whether single nucleotide polymorphisms (SNPs) in melatonin candidate genes contribute to interindividual variation in glucose change. Hypertensive Caucasians (n = 232) from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study treated with atenolol for 9 weeks were studied. Urinary 6-sulfatoxymelatonin (aMT6s) was measured pre- and posttreatment and normalized to urinary creatinine. Pharmacogenetic effects on glucose change of 160 SNPs in 16 melatonin candidate genes were assessed with multiple linear regression. Atenolol was associated with increased glucose (1.8 ± 10.1mg/dl, P = 0.02) and decreased aMT6s (-4.5 ± 10.1 ng/mg, P < 0.0001). However, the aMT6s change was not correlated with post-atenolol glucose change. SNP rs11649514 in PRKCB was associated with glucose change (P = 1.0×10(-4)). PRKCB is involved in the melatonin-insulin regulatory pathway, and may be important in mediating clinically meaningful atenolol-related hyperglycemia.
- Published
- 2016
38. Response to: Heterogeneous Treatment Response by Race Cannot Be Claimed in the Absence of Evidence
- Author
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Yan Gong, John G. Gums, Gary L. Schwartz, Arlene B. Chapman, Zhiying Wang, Amber L. Beitelshees, Kent R. Bailey, Julie A. Johnson, Mai Mehanna, Rhonda M. Cooper-DeHoff, Stephen T. Turner, and Caitrin W. McDonough
- Subjects
Treatment response ,business.industry ,MEDLINE ,Blood Pressure ,Bioinformatics ,Black or African American ,Race (biology) ,Text mining ,Blood pressure ,Hypertension ,Renin ,Internal Medicine ,Humans ,Medicine ,business ,Biomarkers - Published
- 2019
39. Blood pressure signature genes and blood pressure response to thiazide diuretics: results from the PEAR and PEAR-2 studies
- Author
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John G. Gums, Rhonda M. Cooper-DeHoff, Julie A. Johnson, Eric Boerwinkle, Amy Webb, Caitrin W. McDonough, Arlene B. Chapman, Mohamed H. Shahin, Amber L. Beitelshees, Taimour Y. Langaee, Ana Caroline C. Sá, Somnath Datta, Wolfgang Sadee, Steven E. Scherer, Yan Gong, and Stephen T. Turner
- Subjects
Male ,Thiazide diuretics ,0301 basic medicine ,lcsh:Internal medicine ,medicine.medical_specialty ,lcsh:QH426-470 ,Sodium Chloride Symporter Inhibitors ,Blood Pressure ,eQTL ,03 medical and health sciences ,Hydrochlorothiazide ,Internal medicine ,Gene expression ,Genetics ,medicine ,Humans ,RNA-Seq ,lcsh:RC31-1245 ,Antihypertensive Agents ,Genetics (clinical) ,Chromosome 12 ,Thiazide ,Whole blood ,PEAR ,business.industry ,Gene Expression Profiling ,Middle Aged ,Personalized medicine ,Pharmacogenomic Testing ,3. Good health ,lcsh:Genetics ,030104 developmental biology ,Blood pressure ,Endocrinology ,Hypertension ,Female ,Chlorthalidone ,Pharmacogenomics ,business ,Research Article ,medicine.drug - Abstract
Background Recently, 34 genes had been associated with differential expression relative to blood pressure (BP)/ hypertension (HTN). We hypothesize that some of the genes associated with BP/HTN are also associated with BP response to antihypertensive treatment with thiazide diuretics. Methods We assessed these 34 genes for association with differential expression to BP response to thiazide diuretics with RNA sequencing in whole blood samples from 150 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 studies. PEAR white and PEAR-2 white and black participants (n = 50 for each group) were selected based on the upper and lower quartile of BP response to hydrochlorothiazide (HCTZ) and to chlorthalidone. Results FOS, DUSP1 and PPP1R15A were differentially expressed across all cohorts (meta-analysis p-value
- Published
- 2018
40. Evaluation of SAMe-TT
- Author
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Andrew Y, Hwang, Nicholas W, Carris, Eric A, Dietrich, John G, Gums, and Steven M, Smith
- Subjects
Male ,Time Factors ,Anticoagulants ,Pilot Projects ,Middle Aged ,Risk Factors ,Atrial Fibrillation ,Feasibility Studies ,Humans ,Female ,Thrombolytic Therapy ,International Normalized Ratio ,Prospective Studies ,Warfarin ,Drug Monitoring ,Blood Coagulation ,Aged ,Follow-Up Studies ,Forecasting - Abstract
In patients with stable international normalized ratios, 12-week extended-interval warfarin monitoring can be considered; however, predictors of success with this strategy are unknown. The previously validated SAMe-TTTo evaluate the ability of the SAMe-TTIn this post hoc analysis of a single-arm feasibility study, baseline SAMe-TTA total of 47 patients receiving chronic anticoagulation completed a median of 36 weeks of extended-interval follow-up. The median baseline SAMe-TT
- Published
- 2018
41. Genome‐Wide Association Approach Identified Novel Genetic Predictors of Heart Rate Response to β‐Blockers
- Author
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Daniela J. Conrado, Daniel Gonzalez, Stephen T. Turner, Maximilian T. Lobmeyer, Julie A. Johnson, Eric Boerwinkle, Amber L. Beitelshees, Yan Gong, Mohamed H. Shahin, Rhonda M. Cooper-DeHoff, John G. Gums, and Arlene B. Chapman
- Subjects
Adult ,Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Genotype ,Pharmacogenomic Variants ,Single-nucleotide polymorphism ,Genome-wide association study ,β‐blockers ,Receptors, Odorant ,Polymorphism, Single Nucleotide ,White People ,Genetic, Association Studies ,03 medical and health sciences ,Heart Rate ,Cardiovascular Disease ,Internal medicine ,Heart rate ,Genetics ,medicine ,Humans ,SNP ,Sorting Nexins ,Original Research ,Randomized Controlled Trials as Topic ,Metoprolol ,Genetic association ,pharmacogenomics ,business.industry ,Middle Aged ,Atenolol ,metoprolol ,Adrenergic beta-1 Receptor Antagonists ,atenolol ,Black or African American ,Phenotype ,030104 developmental biology ,Pharmacogenetics ,Pharmacogenomics ,Hypertension ,Female ,Cardiology and Cardiovascular Medicine ,business ,Genome-Wide Association Study ,medicine.drug - Abstract
Background For many indications, the negative chronotropic effect of β‐blockers is important to their efficacy, yet the heart rate ( HR ) response to β‐blockers varies. Herein, we sought to use a genome‐wide association approach to identify novel single nucleotide polymorphisms ( SNP s) associated with HR response to β‐blockers. Methods and Results We first performed 4 genome‐wide association analyses for HR response to atenolol (a β1‐adrenergic receptor blocker) as: (1) monotherapy or (2) add‐on therapy, in 426 whites and 273 blacks separately from the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) study. A meta‐analysis was then performed between the genome‐wide association analysis performed in PEAR atenolol monotherapy and add‐on therapy, in each race separately, using the inverse variance method assuming fixed effects. From this analysis, SNP s associated with HR response to atenolol at a P SNP rs17117817 near olfactory receptor family10 subfamily‐p‐member1 ( OR 10P1 ), and SNP rs2364349 in sorting nexin‐9 ( SNX 9 ) replicated in blacks. The combined studies meta‐analysis P values for the rs17117817 and rs2364349 reached genome‐wide significance (rs17117817G‐allele; Meta‐β=5.53 beats per minute, Meta‐ P =2E‐09 and rs2364349 A‐allele; Meta‐β=3.5 beats per minute, Meta‐ P =1E‐08). Additionally, SNP s in the OR 10P1 and SNX 9 gene regions were also associated with HR response in whites. Conclusions This study highlights OR 10P1 and SNX 9 as novel genes associated with changes in HR in response to β‐blockers. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00246519.
- Published
- 2018
42. Betrixaban: A New Oral Factor Xa Inhibitor for Extended Venous Thromboembolism Prophylaxis in High-Risk Hospitalized Patients
- Author
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John G. Gums, Scott Garland, Christina E. DeRemer, and Steven M. Smith
- Subjects
medicine.medical_specialty ,medicine.drug_mechanism_of_action ,Hospitalized patients ,medicine.drug_class ,Pyridines ,Factor Xa Inhibitor ,030204 cardiovascular system & hematology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pharmacokinetics ,Internal medicine ,Medicine ,Humans ,Pharmacology (medical) ,030212 general & internal medicine ,Randomized Controlled Trials as Topic ,business.industry ,Anticoagulant ,Venous Thromboembolism ,Treatment Outcome ,chemistry ,Betrixaban ,Benzamides ,business ,Venous thromboembolism ,Factor Xa Inhibitors - Abstract
Objective: To review the pharmacology, pharmacokinetics, efficacy, and safety of the factor Xa (FXa) inhibitor betrixaban for extended-duration prophylaxis of acute medically ill patients with venous thromboembolism (VTE) risk factors. Data Sources: A MEDLINE/PubMed (January 1990 to October 2017) search was conducted using the following keywords: betrixaban, PRT054021, FXa inhibitor, novel oral anticoagulant, NOAC, direct oral anticoagulant, DOAC, and target specific oral anticoagulant, TSOAC. References of identified articles were searched by hand for additional relevant citations. Study Selection and Data Extraction: We included English-language articles evaluating betrixaban pharmacology, pharmacokinetics, efficacy, or safety in human subjects for VTE prophylaxis. Data Synthesis: Betrixaban is a FXa inhibitor that decreases prothrombinase activity and thrombin generation. Betrixaban efficacy and safety has been compared with that of enoxaparin for prophylaxis of VTE in acutely ill medical patients. In the APEX trial and substudies, extended-duration betrixaban was superior in efficacy to standard-duration enoxaparin in patients at high risk for VTE, including those with elevated D-dimer levels (≥2× upper limit of normal) and of older age (≥75 years). Betrixaban is noninferior to enoxaparin in rates of major bleeding, but the former is associated with more clinically relevant nonmajor bleeding events. Conclusion: Betrixaban is the first oral agent approved for extended-duration VTE prophylaxis in acutely ill hospitalized patients. Extended-duration thromboprophylaxis with betrixaban reduces the risk of VTE compared with standard-duration thromboprophylaxis with enoxaparin but is associated with increased risk of bleeding.
- Published
- 2018
43. Infectious vaginitis
- Author
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Michelle A, Goode, Ken, Grauer, and John G, Gums
- Abstract
Preview Until recently, vaginal candidiasis was generally managed with topical preparations, whereas trichomoniasis and bacterial vaginosis required systemic therapy. Now both topical and systemic therapies are available for vaginal candidiasis and bacterial vaginosis, although systemic therapy is still recommended for trichomoniasis. This article reviews considerations in selecting the most appropriate therapy, including drug efficacy, history of recurrence, ease of administration, and cost.
- Published
- 2017
44. The benefits of physician-pharmacist collaboration
- Author
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Andrew Y, Hwang, Tyler H, Gums, and John G, Gums
- Subjects
Primary Health Care ,Cost-Benefit Analysis ,Interprofessional Relations ,Physicians ,Chronic Disease ,Hypertension ,Humans ,Cooperative Behavior ,Pharmacists ,Antihypertensive Agents - Abstract
Over the past decade, physician-pharmacist collaborative practices have gained traction in primary care as a way to implement team-based-care models. And there is evidence pointing to the effectiveness of this multidisciplinary heath care team approach, in which pharmacists are typically responsible for such things as obtaining medication histories, identifying barriers to adherence, and adjusting medication regimens. Several studies have shown the significant impact that physician-pharmacist collaborative management (PPCM) can have on blood pressure control among patients with hypertension. Additionally, PPCM may have positive effects on HbA1c reduction and diabetes control, suggesting that benefits may extend to other chronic diseases, too.
- Published
- 2017
45. Sphingolipid Metabolic Pathway Impacts Thiazide Diuretics Blood Pressure Response: Insights From Genomics, Metabolomics, and Lipidomics
- Author
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Oliver Fiehn, Mohamed H. Shahin, Xianlin Han, John G. Gums, Amber L. Beitelshees, Stephen T. Turner, Eric Boerwinkle, Rebecca Baillie, Julie A. Johnson, Daniel M. Rotroff, Alison A. Motsinger-Reif, Yan Gong, Reginald F. Frye, Arlene B. Chapman, Rhonda M. Cooper-DeHoff, and Rima Kaddurah-Daouk
- Subjects
0301 basic medicine ,Adult ,Male ,Siloxanes ,Sodium Chloride Symporter Inhibitors ,Serine C-Palmitoyltransferase ,Blood Pressure ,Cardiorespiratory Medicine and Haematology ,Pharmacology ,Cardiovascular ,03 medical and health sciences ,Genetic, Association Studies ,Metabolomics ,Hydrochlorothiazide ,Cardiovascular Disease ,Lipidomics ,Nitriles ,Genetics ,2.1 Biological and endogenous factors ,Medicine ,Humans ,Aetiology ,Thiazide ,Original Research ,pharmacogenetics ,Sphingolipids ,business.industry ,thiazide diuretics ,Human Genome ,Genomics ,Middle Aged ,Lipid Metabolism ,Prognosis ,Sphingolipid ,Metabolic pathway ,030104 developmental biology ,Blood pressure ,Treatment Outcome ,Hypertension ,Female ,Cardiology and Cardiovascular Medicine ,business ,lipid metabolites ,Pharmacogenetics ,Metabolic Networks and Pathways ,Biotechnology ,medicine.drug - Abstract
Background Although hydrochlorothiazide ( HCTZ ) is a well‐established first‐line antihypertensive in the United States, HCTZ treated patients achieve blood pressure ( BP ) control. Thus, identifying biomarkers that could predict the BP response to HCTZ is critically important. In this study, we utilized metabolomics, genomics, and lipidomics to identify novel pathways and biomarkers associated with HCTZ BP response. Methods and Results First, we conducted a pathway analysis for 13 metabolites we recently identified to be significantly associated with HCTZ BP response. From this analysis, we found the sphingolipid metabolic pathway as the most significant pathway ( P =5.8E‐05). Testing 78 variants, within 14 genes involved in the sphingolipid metabolic canonical pathway, with the BP response to HCTZ identified variant rs6078905, within the SPTLC 3 gene, as a novel biomarker significantly associated with the BP response to HCTZ in whites (n=228). We found that rs6078905 C‐allele carriers had a better BP response to HCTZ versus noncarriers (∆ SBP /∆ DBP : −11.4/−6.9 versus −6.8/−3.5 mm Hg; ∆ SBP P =6.7E‐04; ∆ DBP P =4.8E‐04). Additionally, in blacks (n=148), we found genetic signals in the SPTLC 3 genomic region significantly associated with the BP response to HCTZ ( P HCTZ DBP ‐response ( r =−0.42; P =7E‐03) and SBP ‐response ( r =−0.36; P =2E‐02). Conclusions This study provides insight into potential pharmacometabolomic and genetic mechanisms underlying HCTZ BP response and suggests that SPTLC 3 is a potential determinant of the BP response to HCTZ . Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00246519.
- Published
- 2017
46. Whole Transcriptome Sequencing Analyses Reveal Molecular Markers of Blood Pressure Response to Thiazide Diuretics
- Author
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Ana Caroline C. Sá, Amber L. Beitelshees, Somnath Datta, Taimour Y. Langaee, Yan Gong, Arlene B. Chapman, Julie A. Johnson, John G. Gums, Rhonda M. Cooper-DeHoff, Eric Boerwinkle, Wolfgang Sadee, Caitrin W. McDonough, Amy Webb, Stephen T. Turner, and Steven E. Scherer
- Subjects
CCAAT-Enhancer-Binding Protein-delta ,Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,medicine.drug_class ,lcsh:Medicine ,Blood Pressure ,Article ,03 medical and health sciences ,Hydrochlorothiazide ,Internal medicine ,medicine ,Humans ,RNA, Messenger ,lcsh:Science ,Diuretics ,Antihypertensive drug ,Alleles ,Thiazide ,Whole blood ,Multidisciplinary ,business.industry ,Gene Expression Profiling ,lcsh:R ,Chlorthalidone ,Reproducibility of Results ,Middle Aged ,Uric Acid ,3. Good health ,Gene expression profiling ,Logistic Models ,030104 developmental biology ,Blood pressure ,Gene Expression Regulation ,ROC Curve ,Pharmacogenomics ,Potassium ,lcsh:Q ,Female ,business ,Biomarkers ,Transcription Factors ,medicine.drug - Abstract
Thiazide diuretics (TD) are commonly prescribed anti-hypertensives worldwide. However, A RNA-sequencing in baseline samples from 25 responders and 25 non-responders to hydrochlorothiazide (HCTZ) or chlorthalidone. At FDR adjusted p-value CEBPD (meta-analysis p = 1.8 × 10−11) and TSC22D3 (p = 1.9 × 10−9) were differentially expressed in all 3 cohorts, and explain, in aggregate, 21.9% of response variability to TD. This is the first report of the use of transcriptome-wide sequencing data to identify molecular markers of antihypertensive drug response. These findings support CEBPD and TSC22D3 as potential biomarkers of BP response to TD.
- Published
- 2017
47. Genetic Variants Associated With Uncontrolled Blood Pressure on Thiazide Diuretic/β‐Blocker Combination Therapy in the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) and INVEST (International Verapamil‐SR Trandolapril Study) Trials
- Author
-
Rhonda M. Cooper-DeHoff, Kent R. Bailey, Yan Gong, Eric Boerwinkle, John G. Gums, Michiaki Kubo, Carl J. Pepine, Stephen T. Turner, Amber L. Beitelshees, Oyunbileg Magvanjav, Arlene B. Chapman, Toshihiro Tanaka, Julie A. Johnson, and Caitrin W. McDonough
- Subjects
Male ,0301 basic medicine ,Indoles ,Pharmacogenomic Variants ,Sodium Chloride Symporter Inhibitors ,Vasodilator Agents ,Thiazide diuretic ,Drug Resistance ,Angiotensin-Converting Enzyme Inhibitors ,Blood Pressure ,β‐blockers ,030204 cardiovascular system & hematology ,Pharmacology ,combination therapy ,0302 clinical medicine ,Risk Factors ,Odds Ratio ,Prospective Studies ,Original Research ,PEAR ,thiazide diuretics ,Middle Aged ,Calcium Channel Blockers ,Drug Combinations ,Hydrochlorothiazide ,Treatment Outcome ,Hypertension ,Florida ,Female ,Verapamil SR ,Cardiology and Cardiovascular Medicine ,medicine.drug ,Adult ,Trandolapril ,medicine.medical_specialty ,Georgia ,Adolescent ,Combination therapy ,Adrenergic beta-Antagonists ,Polymorphism, Single Nucleotide ,Aldehyde Dehydrogenase 1 Family ,Young Adult ,03 medical and health sciences ,Internal medicine ,genomics ,medicine ,Humans ,Antihypertensive Agents ,Aged ,pharmacogenomics ,Chi-Square Distribution ,business.industry ,Genetic variants ,Retinal Dehydrogenase ,Logistic Models ,030104 developmental biology ,Blood pressure ,Endocrinology ,Atenolol ,Verapamil ,Pharmacogenetics ,Pharmacogenomics ,Multivariate Analysis ,business ,Genome-Wide Association Study ,high blood pressure - Abstract
Background The majority of hypertensive individuals require combination antihypertensive therapy to achieve adequate blood pressure ( BP ) control. This study aimed to identify genetic variants associated with uncontrolled BP on combination therapy with a thiazide diuretic and a β‐blocker. Methods and Results A genome‐wide association study of uncontrolled BP on combination therapy was conducted among 314 white participants of the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) trial. Multivariable logistic regression analysis was used. Genetic variants meeting a suggestive level of significance ( P INVEST (International Verapamil‐ SR Trandolapril study). We also examined genome‐wide variant associations with systolic and diastolic BP response on combination therapy and tested for replication. We discovered a single nucleotide polymorphism, the rs261316 major allele, at chromosome 15 in the gene ALDH1A2 associated with an increased odds of having uncontrolled BP on combination therapy (odds ratio: 2.56, 95% confidence interval, 1.69–3.88, P =8.64E‐06). This single nucleotide polymorphism replicated (odds ratio: 1.86, 95% confidence interval, 1.35–2.57, P =0.001) and approached genome‐wide significance in the meta‐analysis between discovery and replication cohorts (odds ratio: 2.16, 95% confidence interval, 1.63–2.86, P =8.60E‐08). Other genes in the region surrounding rs261316 ( ALDH1A2) include AQP9 and LIPC . Conclusions A single nucleotide polymorphism in the gene ALDH1A2 may be associated with uncontrolled BP following treatment with a thiazide diuretic/β‐blocker combination. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT 00246519.
- Published
- 2017
48. Genetic Variants Influencing Plasma Renin Activity in Hypertensive Patients From the PEAR Study (Pharmacogenomic Evaluation of Antihypertensive Responses)
- Author
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Amelia N. Deitchman, Marina Kawaguchi-Suzuki, Ravi Shankar Prasad Singh, Julie A. Johnson, Stephen T. Turner, Rhonda M. Cooper-DeHoff, Caitrin W. McDonough, Kent R. Bailey, Wolfgang Sadee, Oyunbileg Magvanjav, Yong Shen, Eric Boerwinkle, Wenbin Mei, Chintan V. Dave, Amy Webb, Nihal El Rouby, Ana C.C. Sá, Arlene B. Chapman, Mohamed Hassan M. Solayman, Yan Gong, John G. Gums, and Steven E. Scherer
- Subjects
0301 basic medicine ,Adult ,Male ,Adolescent ,Pharmacogenomic Variants ,Single-nucleotide polymorphism ,Blood Pressure ,030204 cardiovascular system & hematology ,Pharmacology ,Plasma renin activity ,Polymorphism, Single Nucleotide ,Article ,Renin-Angiotensin System ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Hydrochlorothiazide ,Renin–angiotensin system ,Renin ,medicine ,Humans ,Prospective Studies ,Antihypertensive Agents ,Aged ,business.industry ,General Medicine ,Middle Aged ,Atenolol ,United States ,030104 developmental biology ,Blood pressure ,Treatment Outcome ,Pharmacogenetics ,Pharmacogenomics ,Hypertension ,business ,medicine.drug ,Genome-Wide Association Study - Abstract
Background: Plasma renin is an important regulator of blood pressure (BP). Plasma renin activity (PRA) has been shown to correlate with variability in BP response to antihypertensive agents. We conducted a genome-wide association study to identify single-nucleotide polymorphisms (SNPs) associated with baseline PRA using data from the PEAR study (Pharmacogenomic Evaluation of Antihypertensive Responses). Methods: Multiple linear regression analysis was performed in 461 whites and 297 blacks using an additive model, adjusting for age, sex, and ancestry-specific principal components. Top SNPs were prioritized by testing the expected direction of association for BP response to atenolol and hydrochlorothiazide. Top regions from the BP response prioritization were tested for functional evidence through differences in gene expression by genotype using RNA sequencing data. Regions with functional evidence were assessed for replication with baseline PRA in an independent study (PEAR-2). Results: Our top SNP rs3784921 was in the SNN-TXNDC11 gene region. The G allele of rs3784921 was associated with higher baseline PRA (β=0.47; P =2.09×10 −6 ) and smaller systolic BP reduction in response to hydrochlorothiazide (β=2.97; 1-sided P =0.006). In addition, TXNDC11 expression differed by rs3784921 genotype ( P =0.007), and rs1802409, a proxy SNP for rs3784921 ( r 2 =0.98–1.00), replicated in PEAR-2 (β=0.15; 1-sided P =0.038). Additional SNPs associated with baseline PRA that passed BP response prioritization were in/near the genes CHD9, XIRP2, and GHR. Conclusions: We identified multiple regions associated with baseline PRA that were prioritized through BP response signals to 2 mechanistically different antihypertensive drugs. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00246519.
- Published
- 2017
49. Predictors for Glucose Change in Hypertensive Participants Following Short-term Treatment with Atenolol or Hydrochlorothiazide
- Author
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Yan Gong, Karen Hall, Robert Whitney Curry, Wei Hou, John G. Gums, Julie A. Johnson, Eric Boerwinkle, Gary L. Schwartz, Amber L. Beitelshees, Stephen T. Turner, Kent R. Bailey, Siegfried Schmidt, Arlene B. Chapman, Rhonda M. Cooper-DeHoff, and Mariellen J. Moore
- Subjects
Adult ,Blood Glucose ,Male ,Risk ,medicine.medical_specialty ,medicine.drug_class ,Left ventricular hypertrophy ,Models, Biological ,Article ,Cohort Studies ,Hydrochlorothiazide ,Internal medicine ,Diabetes mellitus ,Glucose Intolerance ,medicine ,Humans ,Pharmacology (medical) ,Diuretics ,Antihypertensive drug ,Antihypertensive Agents ,Thiazide ,business.industry ,Middle Aged ,Atenolol ,medicine.disease ,Impaired fasting glucose ,Adrenergic beta-1 Receptor Antagonists ,United States ,Endocrinology ,Blood pressure ,ROC Curve ,Hyperglycemia ,Hypertension ,Drug Therapy, Combination ,Female ,business ,medicine.drug - Abstract
The hyperglycemia associated with the most commonly prescribed antihypertensive drug classes is of growing concern to the medical community. It is well documented that β-blockers and thiazide diuretics cause adverse metabolic effects, and large-scale studies and meta-analyses provide compelling data indicating that β-blockers and thiazide diuretics increase the risk of diabetes.1–5 The ability to discern which participants are at greatest risk for hyperglycemia associated with β-blockers and thiazide diuretics or the development of diabetes would be valuable to clinicians4,6–9. Previous studies found that African ancestry, higher body mass index, left ventricular hypertrophy, higher follow-up systolic blood pressure, elevated baseline glucose, uric acid, female sex, and age are associated with the development of diabetes after long-term β-blocker and/or thiazide diuretic therapy. 3, 4, 10, 11 One study found that African ancestry, lower baseline glucose, and urinary sodium excretion were significant predictors for change in glucose after hydrochlorothiazide (HCTZ) monotherapy.12 To date, no studies have evaluated predictors for glucose change associated with β-blockers. Given that hyperglycemia and diabetes associated with the use of thiazide diuretics and β-blockers may offset the clinical benefit of these two drug classes,10, 13–15 it is important to identify the clinical characteristics that increase risk. If such factors could be identified, they might be useful to guide selection of antihypertensive therapy. Therefore, the goal of the current study was to determine the clinical characteristics associated with change in glucose and impaired fasting glucose (IFG) following treatment with atenolol or HCTZ.
- Published
- 2014
50. Alteration in fasting glucose after prolonged treatment with a thiazide diuretic
- Author
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Marian C. Limacher, Meghan J. Arwood, Rhonda M. Cooper-DeHoff, Julie A. Johnson, Karen Hall, John G. Gums, Jason H. Karnes, and Yan Gong
- Subjects
Adult ,Blood Glucose ,Male ,medicine.medical_specialty ,Time Factors ,Adolescent ,Endocrinology, Diabetes and Metabolism ,Thiazide diuretic ,Article ,Fasting glucose ,Young Adult ,Endocrinology ,Hydrochlorothiazide ,Internal medicine ,Diabetes mellitus ,Diabetes Mellitus ,Internal Medicine ,medicine ,Humans ,Young adult ,Diuretics ,Thiazide ,Aged ,business.industry ,Fasting ,General Medicine ,Middle Aged ,medicine.disease ,Hypertension ,Female ,Chlorthalidone ,business ,Prolonged treatment ,Follow-Up Studies ,medicine.drug - Abstract
Thiazide diuretics are recommended as first line antihypertensive treatment, but may contribute to new onset diabetes. We aimed to describe change in fasting glucose (FG) during prolonged thiazide treatment in an observational setting.We conducted an observational, non-randomized, open label, follow-up study of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 studies. We enrolled previous participants from the PEAR or PEAR-2 studies with at least 6 months of continuous treatment with either hydrochlorothiazide (HCTZ) or chlorthalidone. Linear regression was used to identify associations with changes in FG after prolonged thiazide and thiazide-like diuretic treatment.A total of 40 participants were included with a mean 29 (range 8-72) months of thiazide treatment. FG increased 6.5 (SD 13.0) mg/dL during short-term thiazide treatment and 3.6 (SD 15.3) mg/dL FG during prolonged thiazide treatment. Increased FG at follow-up was associated with longer thiazide treatment duration (β=0.34, p=0.008) and lower baseline FG (β=-0.46, p=0.02). β blocker treatment in combination with prolonged thiazide diuretic treatment was also associated with increased FG and increased 2-h glucose obtained from OGTT.Our results indicate that prolonged thiazide treatment duration is associated with increased FG and that overall glycemic status worsens when thiazide/thiazide-like diuretics are combined with β blockers.
- Published
- 2014
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