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Background— The 5-amino acid (AA) signature, including isoleucine, leucine, valine, tyrosine, and phenylalanine, has been associated with incident diabetes mellitus and insulin resistance. We investigated whether this same AA signature, single-nucleotide polymorphisms in genes in their catabolic pathway, was associated with development of impaired fasting glucose (IFG) after atenolol treatment. Methods and Results— Among 234 European American participants enrolled in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study and treated with atenolol for 9 weeks, we prospectively followed a nested cohort that had both metabolomics profiling and genotype data available for the development of IFG. We assessed the association between baseline circulating levels of isoleucine, leucine, valine, tyrosine, and phenylalanine, as well as single-nucleotide polymorphisms in branched-chain amino-acid transaminase 1 (BCAT1) and phenylalanine hydroxylase (PAH ) with development of IFG. All baseline AA levels were strongly associated with IFG development. Each increment in standard deviation of the 5 AAs was associated with the following odds ratio and 95% confidence interval for IFG based on a fully adjusted model: isoleucine 2.29 (1.31–4.01), leucine 1.80 (1.10–2.96), valine 1.77 (1.07–2.92), tyrosine 2.13 (1.20–3.78), and phenylalanine 2.04 (1.16–3.59). The composite P value was 2×10 −5 . Those with PAH (rs2245360) AA genotype had the highest incidence of IFG ( P for trend=0.0003). Conclusions— Our data provide important insight into the metabolic and genetic mechanisms underlying atenolol-associated adverse metabolic effects. Clinical Trial Registration— http://www.clinicaltrials.gov ; Unique Identifier: NCT00246519

Metoprolol is a selective β-1 adrenergic receptor blocker that undergoes extensive metabolism by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6). Our objective was to investigate the influence of CYP2D6 polymorphisms on the efficacy and tolerability of metoprolol tartrate. Two hundred and eighty-one participants with uncomplicated hypertension received 50 mg of metoprolol twice daily followed by response-guided titration to 100 mg twice daily. Phenotypes were assigned based on results of CYP2D6 genotyping and copy number variation assays. Clinical response to metoprolol and adverse effect rates were analyzed in relation to CYP2D6 phenotypes using appropriate statistical tests. Heart rate response differed significantly by CYP2D6 phenotype (P < 0.0001), with poor and intermediate metabolizers showing greater reduction. However, blood pressure response and adverse effect rates were not significantly different by CYP2D6 phenotype. Other than a significant difference in heart rate response, CYP2D6 polymorphisms were not determinants of variability in metoprolol response or tolerability. Clinical Pharmacology & Therapeutics (2014); 96 2, 175–181. doi:10.1038/clpt.2014.62

Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ∼50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10-7) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification. © 2014 The American Society of Human Genetics.

Elevations in uric acid (UA) and the associated hyperuricaemia are commonly observed secondary to treatment with thiazide diuretics. We sought to identify novel single nucleotide polymorphisms (SNPs) associated with hydrochlorothiazide (HCTZ)-induced elevations in UA and hyperuricaemia.A genome-wide association study of HCTZ-induced changes in UA was performed in Caucasian and African American participants from the pharmacogenomic evaluation of antihypertensive responses (PEAR) study who were treated with HCTZ monotherapy. Suggestive SNPs were replicated in Caucasians and African Americans from the PEAR study who were treated with HCTZ add-on therapy. Replicated regions were followed up through expression and pathway analysis.Five unique gene regions were identified in African Americans (LUC7L2, ANKRD17/COX18, FTO, PADI4 and PARD3B), and one region was identified in Caucasians (GRIN3A). Increases in UA of up to 1.8 mg dL(-1) were observed following HCTZ therapy in individuals homozygous for risk alleles, with heterozygotes displaying an intermediate phenotype. Several risk alleles were also associated with an increased risk of HCTZ-induced clinical hyperuricaemia. A composite risk score, constructed in African Americans using the 'top' SNP from each gene region, was strongly associated with HCTZ-induced UA elevations (P = 1.79 × 10(-7) ) and explained 11% of the variability in UA response. Expression studies in RNA from whole blood revealed significant differences in expression of FTO by rs4784333 genotype. Pathway analysis showed putative connections between many of the genes identified through common microRNAs.Several novel gene regions were associated with HCTZ-induced UA elevations in African Americans (LUC7L2, COX18/ANKRD17, FTO, PADI4 and PARD3B), and one region was associated with these elevations in Caucasians (GRIN3A).

The direct acting oral anticoagulants (DOACs), including dabigatran, rivaroxaban, apixaban, and edoxaban, have favorable pharmacokinetic and pharmacodynamic properties and equal or superior efficacy and an improved safety profile compared with warfarin. Noted shortcomings with DOACs are shorter half-lives requiring stricter adherence, lack of standardized laboratory monitoring, lack of anticoagulation reversal agents, and loss of routine coagulation monitoring leading to fewer patient-clinician interactions. This review addresses many of these limitations including monitoring of DOACs for efficacy and toxicity, an assessment of selected qualitative and quantitative tests, and development of monitoring strategies for special populations. Coagulation monitoring is generally recommended only in overdose situations, but once standardized assays are readily available, they could be helpful to ensure efficacy, assess bleeding, and aid in drug selection in a number of other patient scenarios. Coagulation tests that may provide qualitative assessment include activated partial thromboplastin time, prothrombin time, and thrombin time. Methods with potential utility for quantitative assessment of DOACs include plasma drug concentrations, ecarin clotting time, dilute thrombin time, and anti-factor Xa concentrations. Noncoagulation laboratory monitoring should include serum creatinine, liver function tests, and complete blood counts. Clinical monitoring of the DOAC-treated patient should include routine assessment of adherence, bleeding risks, and drug interactions. Frequency of monitoring should be 1-3 months after initiation and then at least every 6 months, with more frequent follow-up (i.e., 3 months) based on patient specific characteristics such as age, renal impairment, hepatic impairment, and concomitant drug therapy. The authors provide a practical tool to assist in DOAC monitoring and recommend that pharmacists collaborate with physicians in selecting appropriate patients and tailoring patient-specific monitoring plans.

© 2019 Cunningham et al. Background Hypertension (HTN) disproportionately affects African Americans (AAs), who respond better to thiazide diuretics than other antihypertensives. Variants of the APOL1 gene found in AAs are associated with a higher rate of kidney disease and play a complex role in cardiovascular disease. Methods AA subjects from four HTN trials (n = 961) (GERA1, GERA2, PEAR1, and PEAR2) were evaluated for blood pressure (BP) response based on APOL1 genotype after 4–9 weeks of monotherapy with thiazides, beta blockers, or candesartan. APOL1 G1 and G2 variants were determined by direct sequencing or imputation. Results Baseline systolic BP (SBP) and diastolic BP (DBP) levels did not differ based on APOL1 genotype. Subjects with 1–2 APOL1 risk alleles had a greater SBP response to candesartan (-12.2 +/- 1.2 vs -7.5 +/- 1.8 mmHg, p = 0.03; GERA2), and a greater decline in albuminuria with candesartan (-8.3 +/- 3.1 vs +3.7 +/- 4.3 mg/day, p = 0.02). APOL1 genotype did not associate with BP response to thiazides or beta blockers. GWAS was performed to determine associations with BP response to candesartan depending on APOL1 genotype. While no SNPs reached genome wide significance, SNP rs10113352, intronic in CSMD1, predicted greater office SBP response to candesartan (p = 3.7 x 10−7) in those with 1–2 risk alleles, while SNP rs286856, intronic in DPP6, predicted greater office SBP response (p = 3.2 x 10−7) in those with 0 risk alleles. Conclusions Hypertensive AAs without overt kidney disease who carry 1 or more APOL1 risk variants have a greater BP and albuminuria reduction in response to candesartan therapy. BP response to thiazides or beta blockers did not differ by APOL1 genotype. Future studies confirming this initial finding in an independent cohort are required. PEAR1 and PEAR2 was supported by a grant from the National Institutes of Health (https://www.nih.gov/), grant U01 GM074492, funded as part of the Pharmacogenetics Research Network (JAJ). PEAR1 was also supported by the following grants from the NIH National Center for Research Resources: grant M01 RR00082 and UL1 RR029890 to the University of Florida, grants UL1 RR025008 and M01 RR00039 (ABC) to Emory University, and UL1 RR024150 to Mayo Clinic. PEAR2 was also supported by the National Center for Advancing Translational Sciences under the award number UL1 TR000064 (University of Florida); UL1 TR000454 (Emory University) and UL1 TR000135 (Mayo Clinic), and the Mayo Foundation. GERA was supported by NIH grants HL74735, HL53330 (STT), and the Mayo Foundation (https://www.mayo.edu/research).

To identify novel genes influencing blood pressure response to thiazide diuretic therapy for hypertension, we conducted genome-wide association meta-analyses of ≈1.1 million single-nucleotide polymorphisms in a combined sample of 424 European Americans with primary hypertension treated with hydrochlorothiazide from the Pharmacogenomic Evaluation of Antihypertensive Responses study (n=228) and the Genetic Epidemiology of Responses to Antihypertensive study (n=196). Polymorphisms associated with blood pressure response at P –5 were tested for replication of the associations in independent samples of hydrochlorothiazide-treated European hypertensives. The rs16960228 polymorphism in protein kinase C, α replicated for same-direction association with diastolic blood pressure response in the Nordic Diltiazem study (n=420) and the Genetics of Drug Responsiveness in Essential Hypertension study (n=206), and the combined 4-study meta-analysis P value achieved genome-wide significance ( P =3.3×10 −8 ). Systolic or diastolic blood pressure responses were consistently greater in carriers of the rs16960228 A allele than in GG homozygotes (>4/4 mm Hg) across study samples. The rs2273359 polymorphism in the GNAS-EDN3 region also replicated for same-direction association with systolic blood pressure response in the Nordic Diltiazem study, and the combined 3-study meta-analysis P value approached genome-wide significance ( P =5.5×10 −8 ). The findings document clinically important effects of genetic variation at novel loci on blood pressure response to a thiazide diuretic, which may be a basis for individualization of antihypertensive drug therapy and identification of new drug targets.

background Night blood pressure (BP) predicts patient outcomes. Variables associated with night BP response to antihypertensive agents have not been fully evaluated in essential hypertension. methods We sought to measure night BP responses to hydrochlorothiazide (HCTZ), atenolol (ATEN), and combined therapy using ambulatory blood pressure (ABP) monitoring in 204 black and 281 white essential hypertensive patients. Initial therapy was randomized; HCTZ and ATEN once daily doses were doubled after 3 weeks and continued for 6 more weeks with the alternate medication added for combined therapy arms. ABP was measured at baseline and after completion of each drug. Night, day, and night/day BP ratio responses (treatment − baseline) were compared in race/sex subgroups. results Baseline night systolic BP and diastolic BP, and night/day ratios were greater in blacks than whites (P < 0.01, all comparisons). Night BP responses to ATEN were absent and night/day ratios increased significantly in blacks (P < 0.05). At the end of combined therapy, women, blacks, and those starting with HCTZ as opposed to ATEN had significantly greater night BP responses (P < 0.01). Variables that significantly associated with ATEN response differed from those that associated with HCTZ response and those that associated with night BP response differed from those that associated with day BP response. conclusions In summary, after completion of HCTZ and ATEN therapy, women, blacks, and those who started with HCTZ had greater night BP responses. Reduced night BP response and increased night/day BP ratios occured with ATEN in blacks. Given the prognostic significance of night BP, strategies for optimizing night BP antihypertensive therapy should be considered.

Single-nucleotide polymorphisms (SNPs) in NEDD4L may influence the ability of the NEDD4L protein to reduce epithelial sodium channel expression. A variant in NEDD4L, rs4149601, was associated with antihypertensive response and cardiovascular outcomes during treatment with thiazide diuretics and β-blockers in a Swedish population. We sought to further evaluate associations between NEDD4L polymorphisms, blood pressure response and cardiovascular outcomes with thiazide diuretics and β-blockers.Four SNPs, rs4149601, rs292449, rs1008899 and rs75982813, were genotyped in 767 patients from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) clinical trial and association was assessed with blood pressure response to hydrochlorothiazide and atenolol. One SNP, rs4149601, was also genotyped in 1345 patients from the International Verapmil SR Trandolapril Study (INVEST), and association was examined with adverse cardiovascular outcomes relative to hydrochlorothiazide treatment.Significant associations or trends were found between rs4149601, rs292449, rs75982813 and rs1008899 and decreases in blood pressure in whites on hydrochlorothiazide, and a significant association was observed with increasing copies of the GC rs4149601-rs292449 haplotype and greater blood pressure response to hydrochlorothiazide in whites (P = 0.0006 and 0.006, SBP and DBP, respectively). Significant associations were also seen with rs4149601 and an increased risk for adverse cardiovascular outcomes in whites not treated with hydrochlorothiazide [P = 0.022, odds ratio (95% confidence interval) = 10.65 (1.18-96.25)].NEDD4L rs4149601, rs292449 and rs75982813 may be predictors for blood pressure response to hydrochlorothiazide in whites, and NEDD4L rs4149601 may be a predictor for adverse cardiovascular outcomes in whites not treated with hydrochlorothiazide.

Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ∼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ∼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10(-6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.

Background— To date, 39 single nucleotide polymorphisms (SNPs) have been associated with blood pressure (BP) or hypertension in genome-wide association studies in whites. Our hypothesis is that the loci/SNPs associated with BP/hypertension are also associated with BP response to antihypertensive drugs. Methods and Results— We assessed the association of these loci with BP response to atenolol or hydrochlorothiazide monotherapy in 768 hypertensive participants in the Pharmacogenomics Responses of Antihypertensive Responses study. Linear regression analysis was performed on whites for each SNP in an additive model adjusting for baseline BP, age, sex, and principal components for ancestry. Genetic scores were constructed to include SNPs with nominal associations, and empirical P values were determined by permutation test. Genotypes of 37 loci were obtained from Illumina 50K cardiovascular or Omni1M genome-wide association study chips. In whites, no SNPs reached Bonferroni-corrected α of 0.0014, 6 reached nominal significance ( P P P =3.3×10 –6 for systolic BP; P =1.6×10 –6 for diastolic BP). The genetic score of the hydrochlorothiazide BP-lowering alleles was associated with response to hydrochlorothiazide ( P =0.0006 for systolic BP; P =0.0003 for diastolic BP). Both risk score P values were Conclusions— These findings suggest that selected signals from hypertension genome-wide association studies may predict BP response to atenolol and hydrochlorothiazide when assessed through risk scoring. Clinical Trial Registration Information— clinicaltrials.gov ; Identifier: NCT00246519.

G protein–coupled receptor kinases (GRKs) are important regulatory proteins for many G protein–coupled receptors, but little is known about GRK4 pharmacogenetics. We hypothesized that 3 nonsynonymous GRK4 single-nucleotide polymorphisms, R65L (rs2960306), A142V (rs1024323), and A486V (rs1801058), would be associated with blood pressure response to atenolol, but not hydrochlorothiazide, and would be associated with long-term cardiovascular outcomes (all-cause death, nonfatal myocardial infarction, nonfatal stroke) in participants treated with an atenolol-based versus verapamil-SR–based antihypertensive strategy. GRK4 single-nucleotide polymorphisms were genotyped in 768 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) trial. In whites and blacks, increasing copies of the variant 65L-142V haplotype were associated with significantly reduced atenolol-induced diastolic blood pressure lowering (−9.1±6.8 versus −6.8±7.1 versus −5.3±6.4 mm Hg in participants with 0, 1, and 2 copies of 65L-142V, respectively; P =0.0088). One thousand four hundred sixty participants with hypertension and coronary artery disease from the INternational VErapamil SR/Trandolapril STudy (INVEST) were genotyped, and variant alleles of all 3 GRK4 single-nucleotide polymorphisms were associated with increased risk for adverse cardiovascular outcomes in an additive fashion, with 486V homozygotes reaching statistical significance (odds ratio, 2.29 [1.48–3.55]; P =0.0002). These effects on adverse cardiovascular outcomes were independent of antihypertensive treatment. These results suggest that the presence of GRK4 variant alleles may be important determinants of blood pressure response to atenolol and risk for adverse cardiovascular events. The associations with GRK4 variant alleles were stronger in patients who were also ADRB1 389R homozygotes, suggesting a potential interaction between these 2 genes.

Atenolol, a commonly prescribed β blocker for hypertension, is also associated with adverse cardiometabolic effects such as hyperglycemia and dyslipidemia. Knowledge of the mechanistic underpinnings of these adverse effects of atenolol is incomplete. We sought to identify biomarkers associated with risk for these untoward effects of atenolol. We measured baseline blood serum levels of acylcarnitines (ACs) that are involved in a host of different metabolic pathways, to establish associations with adverse cardiometabolic responses after atenolol treatment. Serum samples from Caucasian hypertensive patients (n = 224) who were treated with atenolol in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study were interrogated using a quantitative LC/MS assay for a large number of unique ACs in serum. For the 23 ACs that were detected in serum from ≥80 % of all patients, we conducted linear regression for changes in cardiometabolic factors with baseline AC levels, baseline cardiometabolic factors, age, sex, and BMI as covariates. For the 5 ACs that were detected in serum from 20 to 79 % of the patients, we similarly modeled changes in cardiometabolic factors, but with specifying the AC as present/absent in the regression. Among the 28 ACs, the presence (vs. absence) of arachidonoyl-carnitine (C20:4) was significantly associated with increased glucose (p = 0.0002), and was nominally associated with decreased plasma HDL-C (p = 0.017) and with less blood pressure (BP) lowering (p = 0.006 for systolic BP, p = 0.002 for diastolic BP), after adjustment. Serum level of C20:4 is a promising biomarker to predict adverse cardiometabolic responses including glucose and poor antihypertensive response to atenolol.

While atenolol is an effective antihypertensive agent, its use is also associated with adverse events including hyperglycemia and incident diabetes that may offset the benefits of blood pressure lowering. By combining metabolomic and genomic data acquired from hypertensive individuals treated with atenolol, it may be possible to better understand the pathways that most impact the development of an adverse glycemic state. To identify biomarkers that can help predict susceptibility to blood glucose excursions during exposure to atenolol. Plasma samples acquired from 234 Caucasian participants treated with atenolol in the Pharmacogenomic Evaluation of Antihypertensive Responses trial were analyzed by gas chromatography Time-Of-Flight Mass Spectroscopy. Metabolomics and genomics data were integrated by first correlating participant’s metabolomic profiles to change in glucose after treatment with atenolol, and then incorporating genotype information from genes involved in metabolite pathways associated with glucose response. Our findings indicate that the baseline level of β-alanine was associated with glucose change after treatment with atenolol (Q = 0.007, β = 2.97 mg/dL). Analysis of genomic data revealed that carriers of the G allele for SNP rs2669429 in gene DPYS, which codes for dihydropyrimidinase, an enzyme involved in β-alanine formation, had significantly higher glucose levels after treatment with atenolol when compared with non-carriers (Q = 0.05, β = 2.76 mg/dL). This finding was replicated in participants who received atenolol as an add-on therapy (P = 0.04, β = 1.86 mg/dL). These results suggest that β-alanine and rs2669429 may be predictors of atenolol-induced hyperglycemia in Caucasian individuals and further investigation is warranted.

Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids. © 2012 The American Society of Human Genetics.

Extended-interval monitoring of warfarin has been proposed to reduce follow-up burden and improve patient satisfaction. We aimed to make an initial assessment of anticoagulation satisfaction before and after an extended-interval warfarin monitoring intervention. We conducted a translational prospective single-arm pilot study of extended-interval warfarin monitoring in five pharmacist-managed anticoagulation clinics. Patients meeting CHEST guideline criteria for extended-interval warfarin monitoring began progressive extended-interval follow-up (6, 8, and 12 weeks thereafter). The Duke Anticoagulation Satisfaction Scale (DASS) was administered at baseline and at end-of-study or study removal (in patients no longer appropriate for extended interval follow-up). Forty-six patients had evaluable pre- and post-intervention DASS survey data. Mean age of patients was 66.5 years, 74 % were non-Hispanic whites, and 48 % were men. Patients completed a mean ± SD of 34 ± 22 weeks of follow-up. Mean ± SD total DASS score at baseline was 45.2 ± 14.2 versus 49.1 ± 14.9 at end-of-study (mean change, +3.9 [95 % CI −0.6–8.4; p = 0.09]), indicating no benefit—and trending toward decrement—to anticoagulation satisfaction. Change in anticoagulation satisfaction varied substantially following extended-interval monitoring, with no evidence of improved satisfaction. Plausible reasons for patients not preferring extended-interval monitoring include increased anxiety and disengagement from self-management activities, both potentially related to less frequent feedback and reassurance during extended interval-monitoring. Additional research is needed to identify who is likely to benefit most from extended-interval monitoring. Anticoagulation satisfaction should be considered with clinical factors and shared-decision making when implementing extended-interval warfarin monitoring.

Background— Thiazide diuretics are among the most commonly prescribed antihypertensives. However, Methods and Results— Genome-wide analysis included 228 white hypertensives with BP determined at baseline and after 9 weeks of hydrochlorothiazide. Single-nucleotide polymorphisms with P − 5 were prioritized according to their biological function, using RegulomeDB, haploreg, and Genome-Wide Annotation of Variants. The results from the prioritization approach revealed rs10995 as the most likely functional single-nucleotide polymorphism, among single-nucleotide polymorphisms tested, that has been associated with hydrochlorothiazide BP response. The rs10995 G -allele was associated with better BP response to hydrochlorothiazide versus noncarriers (Δ systolic BP/Δ diastolic BP: −12.3/−8.2 versus −6.8/−3.5 mm Hg, respectively, Δ systolic BP P =3×10 −4 , Δ diastolic BP P =5×10 −5 ). This association was replicated in independent participants treated with chlorthalidone. In addition, rs10995 G-allele was associated with increased mRNA expression of VASP (vasodilator-stimulated phosphoprotein). Moreover, baseline expression of the VASP mRNA was significantly higher in 25 good responders to hydrochlorothiazide compared with 25 poor responders ( P =0.01). This finding was replicated in independent participants treated with chlorthalidone ( P =0.04). Last, allelic-specific expression analysis revealed a significant but modest imbalance with rs10995 and rs10156, a single-nucleotide polymorphism in high linkage disequilibrium ( r 2 =0.7) with rs10995, which both could contribute to the observed genetic effects by affecting VASP mRNA expression. Conclusions— This study highlights the strength of using different omics to identify novel biomarkers of drug response and suggests VASP as a potential determinant of thiazide diuretics BP response. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifiers: NCT00246519 and NCT01203852.

Hydrochlorothiazide is among the most commonly prescribed antihypertensives; yet, PRKAG2 , rs12604940 DCC , and rs13262930 EPHX2 ) along with arachidonic acid, converging in the netrin signaling pathway ( P =1×10 −5 ), as potential markers, significantly influencing hydrochlorothiazide BP response. We successfully replicated the 3 genetic signals in 212 white hypertensives treated with hydrochlorothiazide and created a response score by summing their BP-lowering alleles. We found patients carrying 1 response allele had a significantly lower response than carriers of 6 alleles (∆SBP/∆DBP: −1.5/1.2 versus −16.3/−10.4 mm Hg, respectively, SBP score, P =1×10 −8 and DBP score, P =3×10 −9 ). This score explained 11.3% and 11.9% of the variability in hydrochlorothiazide SBP and DBP responses, respectively, and was further validated in another independent study of 196 whites treated with hydrochlorothiazide (DBP score, P =0.03; SBP score, P =0.07). This study suggests that PRKAG2 , DCC , and EPHX2 might be important determinants of hydrochlorothiazide BP response.

The evolution of antimicrobial resistance is a multifaceted issue that is influenced by numerous factors. This growing healthcare problem has significantly impacted the public welfare and has substantially burdened the economic system on a global scale. In an effort to combat this rising problem, several strategies have been implemented in the recent years to stall the progression and decrease the emergence of antimicrobial resistance. The aim of this review article is to describe the various factors that have contributed to the current state of antimicrobial resistance and to evaluate potential strategies developed to reduce the burden of antimicrobial resistance.

Thiazide-induced potassium loss may contribute to new onset diabetes (NOD). KCNJ1 encodes a potassium channel and one study observed that a KCNJ1 single-nucleotide polymorphism (SNP) was associated with changes in fasting glucose (FG) during hydrochlorothiazide (HCTZ) treatment. We used linear regression to test association of KCNJ1 SNPs and haplotypes with FG changes during HCTZ treatment in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study. We used logistic regression to test association of KCNJ1 variation with NOD in HCTZ-treated patients from the International Verapamil SR Trandolapril Study (INVEST). Multivariate regression analyses were performed by race/ethnicity with false discovery rate (FDR) correction. In PEAR blacks, a KCNJ1 SNP was associated with increased FG during HCTZ treatment (beta = 8.47, PFDR = 0.009). KCNJ1 SNPs and haplotypes were associated with NOD risk in all INVEST race/ethnic groups (strongest association: odds ratio 2.14 (1.31–3.53), PFDR = 0.03). Our findings support that KCNJ1 variation is associated with HCTZ-induced dysglycemia and NOD.

Background/Aims: Hyperuricemia is associated with obesity and the metabolic syndrome. URAT1 is a urate transporter, and we tested the association of URAT1 transporter gene (SLC22A12) polymorphisms with obesity and the metabolic syndrome in hypertensive subjects. Methods: Patients with essential hypertension (n = 414) from a randomized controlled study were genotyped for SLC22A12 SNPs rs11602903, rs505802 and rs11231825. Results: In Caucasians, SLC22A12 SNPs were associated with the body mass index (BMI). rs11602903 was associated with BMI (p < 0.0001), waist circumference (p = 0.003), HDL cholesterol (p = 0.018) and the metabolic syndrome (p = 0.033), and accounted for 7% of the variation of BMI in Caucasians. In African Americans, SLC22A12 SNP rs11602903 was not associated with BMI, waist circumference, HDL cholesterol or triglycerides. Conclusion: The URAT1 gene SLC22A12 polymorphism may play a role in obesity and the metabolic syndrome in Caucasian hypertensive subjects.

Team-based care has been recommended for patients with treatment-resistant hypertension (TRH), but its efficacy in this setting is unknown. We compared a physician-pharmacist collaborative model (PPCM) to usual care in patients with TRH participating in the Collaboration Among Pharmacists and Physicians To Improve Outcomes Now study. At baseline, 169 patients (27% of Collaboration Among Pharmacists and Physicians To Improve Outcomes Now patients) had TRH: 111 received the PPCM intervention and 58 received usual care. Baseline characteristics were similar between treatment arms. After 9 months, adjusted mean systolic blood pressure was reduced by 7 mm Hg more with PPCM intervention than usual care (P = .036). Blood pressure control was 34.2% with PPCM versus 25.9% with usual care (adjusted odds ratio, 1.92; 95% confidence interval, 0.33-11.2). These findings suggest that team-based care in the primary care setting may be effective for TRH. Additional research is needed regarding the long-term impact of these models and to identify patients most likely to benefit from team-based interventions.

Introduction: β-blockers, including atenolol, are among the most widely prescribed antihypertensive drug classes. However, their use has been associated with hyperglycemia and incident diabetes, which poses concern for prescribers and patients. The Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study is a multicenter clinical trial with one of its objectives to identify genetic influences on adverse metabolic events in patients treated with atenolol. Here we report a genomics-metabolomics integrative approach to identify biomarkers associated with atenolol-induced glucose change. Methods: PEAR participants were genotyped using the Illumina Omni 1M-Quad Chip. Metabolite profiles were acquired through GC-TOF-MS. Association between baseline levels of metabolites and glucose change was conducted using a multivariate linear regression model adjusted for age, gender and baseline fasting glucose. Genomics-metabolomics integration included selecting SNPs within genes involved in the synthesis and degradation of top metabolites and testing their effect on glucose change in 234 atenolol-treated Caucasians in PEAR, adjusting for age, gender, baseline glucose and principal components 1 and 2. A false discovery rate (FDR) of .05 was used to adjust for multiple comparisons. Replication of significant SNPs was conducted in an additional 228 participants treated with atenolol in PEAR. Results: Metabolomics analysis revealed 3 metabolites associated with glucose change that passed FDR adjustment. The top metabolite signal was beta-alanine. Increasing levels of baseline beta-alanine was significantly correlated with greater glucose increases after atenolol treatment (p=.0003). A total of 79 SNPs in 12 genes in the beta-alanine pathway were explored. SNP rs2669429 in DPYS was significantly associated with glucose change, after FDR adjustment. We found that G allele carriers had significantly greater glucose change compared with non-carriers (p=.0006; β=+2.76 mg/dL). This finding was successfully replicated in the other 228 patients who received atenolol (p=.04; β=+1.86 mg/dL). Conclusions: These results suggest that beta alanine and DPYS rs2669429 SNP might be an important predictor of atenolol-induced dysglycemia.

The aim of this study is to identify single-nucleotide polymorphisms (SNPs) influencing blood pressure (BP) response to the β-blocker atenolol.Genome-wide association analysis of BP response to atenolol monotherapy was performed in 233 white participants with uncomplicated hypertension in the pharmacogenomic evaluation of antihypertensive responses study. Forty-two polymorphisms with P less than 10 for association with either diastolic or systolic response to atenolol monotherapy were validated in four independent groups of hypertensive individuals (total n = 2114).In whites, two polymorphisms near the gene PTPRD (rs12346562 and rs1104514) were associated with DBP response to atenolol (P = 3.2 × 10 and P = 5.9 × 10, respectively) with directionally opposite association for response to hydrochlorothiazide in another group of 228 whites (P = 0.0018 and P = 0.00012). A different polymorphism (rs10739150) near PTPRD was associated with response to atenolol in 150 black hypertensive individuals (P = 8.25 × 10). rs12346562 had a similar trend in association with response to bisoprolol (a different β-blocker) in 207 Finnish men in the genetics of drug responsiveness in essential hypertension study. In addition, an intronic single-nucleotide polymorphism (rs4742610) in the PTPRD gene was associated with resistant hypertension in whites and Hispanics in the international verapamil SR trandolapril study (meta-analysis P = 3.2 × 10).PTPRD was identified as a novel locus potentially associated with BP response to atenolol and resistant hypertension in multiple ethnic groups.

The G-protein-coupled receptor kinases (GRKs) GRK2 and GRK5 are important regulators of β-adrenergic signaling. This study characterized single-nucleotide polymorphisms (SNPs) in the GRK2 gene (ADRBK1) and determined if these and a GRK5 Gln41Leu polymorphism affect the blood pressure (BP) response to atenolol or hydrochlorothiazide or adverse cardiovascular outcomes in hypertensives.ADRBK1 regions were sequenced for 48 individuals. Putative functional SNPs were tested for mRNA expression differences in 96 lymphoblastoid cell line samples and 12 leukocyte samples from hypertensives. BP response to atenolol and hydrochlorothiazide by ADRBK1 SNPs and GRK5 Gln41Leu was tested in 418 patients from the Pharmacogenomic Evaluation of Antihypertensive Responses Study using linear regression. The influence of ADRBK1 SNPs and GRK5 Gln41Leu on death, myocardial infarction or stroke in treated hypertensives was evaluated in a case-control cohort (1 : 3) of the International Verapamil SR/Trandolapril Study GENEtic Substudy using logistic regression models.A novel ADRBK1 promoter SNP was not associated with differential GRK2 expression. GRK5 Leu41 decreased the risk for adverse cardiovascular outcomes independent of treatment strategy (adjusted odds ratio 0.535, 95% confidence interval: 0.313-0.951, P=0.0222), but was not associated with BP response to antihypertensive medication. An ADRBK1 SNP (rs1894111 GA) showed a signal for association with systolic and diastolic BP response to hydrochlorothiazide in Whites [diastolic BP: -11.29±3.74 (G/A) versus -4.26±4.79 mmHg (G/G), P=0.0034 and systolic BP: -18.37±14.90 (G/A), -8.11±7.55 mmHg (G/G), P=0.0191].The GRK5 Leu41 allele protects from adverse cardiovascular outcomes in treated hypertensives.

Since thiazide diuretics were introduced in the late 1950s for treatment of hypertension, interpatient variation has been documented for blood pressure responses to agents from all classes of antihypertensive drugs.1,2 For any single agent given as monotherapy, ~50% of patients achieve blood pressure levels

Office, home, and ambulatory blood pressure (BP) demonstrate variable associations with outcomes. The authors sought to compare office BP (OBP), home BP (HBP), and ambulatory BP (ABP) for measuring responses to hydrochlorothiazide (HCTZ), atenolol, and their combination. After completing washout, eligible patients were randomized to atenolol 50 mg or HCTZ 12.5 mg daily. Doses were doubled after 3 weeks and the alternate drug was added after 6 weeks if BP was >120/70 mm Hg (chosen to allow maximum opportunity to assess genetic associations with dual BP therapy in the parent study). OBP (in triplicate), HBP (twice daily for 5 days), and 24-hour ABP were measured at baseline, after monotherapy, and after combination therapy. BP responses were compared between OBP, HBP, and ABP for each monotherapy and combination therapy. In 418 patients, OBP overestimated BP response compared with HBP, with an average 4.6 mm Hg greater reduction in systolic BP (P

To assess influenza-related secondary complications and healthcare use and costs in patients prescribed oseltamivir for influenza.This study examined health insurance claims data for patients diagnosed with influenza during five influenza seasons. Patients prescribed oseltamivir were propensity matched with patients not prescribed antiviral therapy.Clinical outcomes were diagnosis with pneumonia, otitis media and hospitalizations, along with in-patient, out-patient and pharmacy use and costs.Each group included 45,751 patients. Patients prescribed oseltamivir had significant reductions in the risks of pneumonia (odds ratio [OR]: 0.89, 95% CI: 0.80, 1.00), otitis media (OR: 0.84, 95% CI: 0.77, 0.91) and hospitalization (OR: 0.71, 95% CI: 0.62, 0.83). The risks of pneumonia and otitis media were also lower in children and adolescents (or = 17 years) prescribed oseltamivir (OR: 0.74, 95% CI: 0.60, 0.91 and OR: 0.77, 95% CI: 0.69, 0.85, respectively). Total healthcare costs were lower for patients prescribed oseltamivir versus no antiviral therapy (mean US$500 versus 510; p0.0001). Patients prescribed oseltamivir had fewer claims per patient for antibiotics (0.37 versus 0.45; p0.0001), fewer physician visits (1.72 versus 1.78; p0.0001), emergency room visits (0.11 versus 0.12; p0.0001), and spent fewer days in hospital (0.04 versus 0.05; p0.0001).The risks of influenza-related complications and hospitalization, as well as healthcare use and costs, were lower for patients prescribed oseltamivir than for those with no antiviral prescription.

Objective: To review data to determine why pneumococcal isolates appear to be increasingly resistant to cefotaxime, historically regarded as having the same in vitro susceptibility to ceftriaxone, and what this observation might imply clinically. Data Sources: Literature was accessed through MEDLINE (1966–October 2007) using the MeSH terms cefotaxime, ceftriaxone, susceptibility, microbial sensitivity tests, antibiotics, pneumococcal infections, Streptococcus pneumoniae. resistance, and cephalosporin resistance. Abstracts and surveillance databases were reviewed and unpublished data were provided by state departments of health and institutions. Study Selection and Data Extraction: All articles published in the English language that were identified from the data sources were evaluated. Data Synthesis: An experimental model of pneumococcal infection in mice conducted 2 decades ago predicted that the delta T minimum inhibitory concentration (MIC) varied less for ceftriaxone than for cefotaxime. Studies of plasma and serum concentrations show that ceftriaxone remains at a concentration above the S. pneumoniae MIC for 100% of the dosing interval al 12 hours. Types of MIC susceptibility test methods for ceftriaxone and cefotaxime used against S pneumoniae respiratory isolates were found to be similar. Data from state and county health departments found microbiological discrepancies between ceftriaxone and cefotaxime. In areas with high rates of penicillin-resistant S. pneumoniae (PRSP), isolates were twice as susceptible to ceftriaxone versus cefotaxime. Surveillance databases consistently show differences between susceptibility of S. pneumoniae to cefotaxime versus ceftriaxone over time. MIC and pulsed-field gel electrophoresis studies suggest that phenotypic discrepancies may account for ponicillin resistance. Ongoing studies are examining S. pneumoniae isolates at the molecular level to determine the basis of difference in resistance to cefotaxime and ceftriaxone. Conclusions: An increase in rates of PRSP and differences in S. pneumoniae isolate susceptibility between ceftriaxone and cefotaxime emphasize the necessity for hospital laboratories to detect these changes as they occur. Clinicians should select the most appropriate agent for patients with S. pneumoniae.

Background Antimicrobial resistance can be tracked by several methods. The optimal application of surveillance strategies is an integral part in curbing the resistance epidemic. Objectives The Antimicrobial Resistance Management (ARM) and Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) programs are ongoing antibiotic surveillance studies with different methodologies. Our aim was to compare susceptibility data generated by each program to determine if the two methods produce similar results. Methods ARM is a Web-based, antibiogram-driven surveillance system, whereas MYSTIC tests individual bacterial isolates in accordance with Clinical Laboratory Standards Institute methods. We compared national susceptibility rates during 1999 to 2004 from ARM and MYSTIC for Escherichia coli and Klebsiella pneumoniae. Results E. coli susceptibility was greater than 90% for all agents evaluated except ciprofloxacin and levofloxacin. Susceptibility rates in ARM and MYSTIC were similar (within 5%), with the exception of levofloxacin — for which susceptibility was reported as 92.3% in ARM and 83% in MYSTIC ( P < 0.0001). Amikacin, cefepime, ceftriaxone, imipenem, and meropenem were identified by both surveillance programs as the most active agents against E. coli and K. pneumoniae. Both systems detected increasing fluoroquinolone resistance ( P < 0.0001) and relatively stable activity among other agents tested. For K. pneumoniae, all agents displayed resistance rates less than 10%. Susceptibility rates in ARM and MYSTIC were remarkably similar. The largest difference was 2.9% for piperacillin/tazobactam (92.8% in ARM vs 95.7% in MYSTIC, P < 0.0001). Regionally, nonsusceptibility to E. coli and K. pneumoniae was similar, though for some comparisons MYSTIC reported higher rates of nonsusceptibility in the Northeast, Northwest, and South Central. Conclusion Surveillance of antibiotic activity patterns can be performed confidently with either method discussed above. Attempts should be made to integrate results from different surveillance programs to optimize surveillance.

African Americans suffer a higher prevalence of hypertension compared with other racial/ethnic groups. In this study, we performed a pharmacogenomic genome-wide association study of blood pressure (BP) response to β-blockers in African Americans with uncomplicated hypertension. Genome-wide meta-analysis was performed in 318 African American hypertensive participants in the 2 Pharmacogenomic Evaluation of Antihypertensive Responses studies: 150 treated with atenolol monotherapy and 168 treated with metoprolol monotherapy. The analysis adjusted for age, sex, baseline BP and principal components for ancestry. Genome-wide significant variants with P –8 and suggestive variants with P –7 were evaluated in an additional cohort of 141 African Americans treated with the addition of atenolol to hydrochlorothiazide treatment. The validated variants were then meta-analyzed in these 3 groups of African Americans. Two variants discovered in the monotherapy meta-analysis were validated in the add-on therapy. African American participants heterozygous for SLC25A31 rs201279313 deletion versus wild-type genotype had better diastolic BP response to atenolol monotherapy, metoprolol monotherapy, and atenolol add-on therapy: −9.3 versus −4.6, −9.6 versus −4.8, and −9.7 versus −6.4 mm Hg, respectively (3-group meta-analysis P =2.5×10 –8 , β=−4.42 mm Hg per variant allele). Similarly, LRRC15 rs11313667 was validated for systolic BP response to β-blocker therapy with 3-group meta-analysis P =7.2×10 –8 and β=−3.65 mm Hg per variant allele. In this first pharmacogenomic genome-wide meta-analysis of BP response to β-blockers in African Americans, we identified novel variants that may provide valuable information for personalized antihypertensive treatment in this group.

Summary Aims The 2012 American College of Chest Physician Evidence-Based Management of Anticoagulant Therapy guidelines suggest an international normalized ratio (INR) testing interval of up to 12 weeks, rather than every 4 weeks, for patients with consistently stable INRs while taking vitamin K antagonists. We aimed to examine the feasibility of extended-interval follow-up in a real-world setting. Methods Patients receiving stable warfarin therapy for ≥12 weeks at baseline began extended-interval follow-up with visits occurring at 6 weeks, 14 weeks, and every 12 weeks thereafter to a maximum of 68 weeks or until they were no longer suitable for extended-interval follow-up. A single INR excursion >0.3 from goal was permitted if a reversible precipitating factor was identified and the INR was expected to return to goal without dose adjustment. The primary outcome was the proportion of patients completing all study follow-up visits. Results Of 48 patients enrolled, 47 had evaluable data. The most common indication for anticoagulation was atrial fibrillation/flutter (53.2%). At baseline, mean prior warfarin treatment duration was 6.7 ± 6 years and median number of weeks on a stable regimen was 24 weeks (IQR, 19–37.5). Eleven patients (23%) completed all study follow-up visits, whereas 17 (36%) did not maintain a stable INR past the 14-week follow-up. Conclusion A large proportion of patients with previously stable (≥3 months) INRs were not able to maintain stable INRs during extended-interval follow-up. More research is needed to identify patient characteristics predictive of success with extended-interval follow-up prior to broad implementation.

Background Identification of genetic markers of antihypertensive drug responses could assist in individualization of hypertension treatment. Methods and Results We conducted a genome‐wide association study to identify gene loci influencing the responsiveness of 228 male patients to 4 classes of antihypertensive drugs. The Genetics of Drug Responsiveness in Essential Hypertension ( GENRES ) study is a double‐blind, placebo‐controlled cross‐over study where each subject received amlodipine, bisoprolol, hydrochlorothiazide, and losartan, each as a monotherapy, in a randomized order. Replication analyses were performed in 4 studies with patients of European ancestry ( PEAR Study, N=386; GERA I and II Studies, N=196 and N=198; SOPHIA Study, N=372). We identified 3 single‐nucleotide polymorphisms within the ACY 3 gene that showed associations with bisoprolol response reaching genome‐wide significance ( P −8 ); however, this could not be replicated in the PEAR Study using atenolol. In addition, 39 single‐nucleotide polymorphisms showed P values of 10 −5 to 10 −7 . The 20 top‐associated single‐nucleotide polymorphisms were different for each antihypertensive drug. None of these top single‐nucleotide polymorphisms co‐localized with the panel of >40 genes identified in genome‐wide association studies of hypertension. Replication analyses of GENRES results provided suggestive evidence for a missense variant (rs3814995) in the NPHS 1 (nephrin) gene influencing losartan response, and for 2 variants influencing hydrochlorothiazide response, located within or close to the ALDH 1A3 (rs3825926) and CLIC 5 (rs321329) genes. Conclusions These data provide some evidence for a link between biology of the glomerular protein nephrin and antihypertensive action of angiotensin receptor antagonists and encourage additional studies on aldehyde dehydrogenase–mediated reactions in antihypertensive drug action.

Background Resistant hypertension (RHTN), defined by lack of blood pressure (BP) control despite treatment with at least 3 antihypertensive drugs, increases cardiovascular risk compared with controlled hypertension. Yet, there are few data on genetic variants associated with RHTN. Methods and Results We used a gene‐centric array containing ≈50 000 single‐nucleotide polymorphisms (SNPs) to identify polymorphisms associated with RHTN in hypertensive participants with coronary artery disease (CAD) from INVEST‐GENES (the INnternational VErapamil‐SR Trandolapril STudy—GENEtic Substudy). RHTN was defined as BP≥140/90 on 3 drugs, or any BP on 4 or more drugs. Logistic regression analysis was performed in European Americans (n=904) and Hispanics (n=837), using an additive model adjusted for age, gender, randomized treatment assignment, body mass index, principal components for ancestry, and other significant predictors of RHTN. Replication of the top SNP was conducted in 241 European American women from WISE (Women's Ischemia Syndrome Evaluation), where RHTN was defined similarly. To investigate the functional effect of rs12817819, mRNA expression was measured in whole blood. We found ATP2B1 rs12817819 associated with RHTN in both INVEST European Americans ( P ‐value=2.44×10 −3 , odds ratio=1.57 [1.17 to 2.01]) and INVEST Hispanics ( P =7.69×10 −4 , odds ratio=1.76 [1.27 to 2.44]). A consistent trend was observed at rs12817819 in WISE, and the INVEST‐WISE meta‐analysis result reached chip‐wide significance ( P =1.60×10 −6 , odds ratio=1.65 [1.36 to 1.95]). Expression analyses revealed significant differences in ATP2B1 expression by rs12817819 genotype. Conclusions The ATP2B1 rs12817819 A allele is associated with increased risk for RHTN in hypertensive participants with documented CAD or suspected ischemic heart disease. Clinical Trial Registration URL: www.clinicaltrials.gov ; Unique identifiers: NCT00133692 (INVEST), NCT00000554 (WISE).

Most patients with diabetes mellitus require multiple medications to achieve glycemic goals. Considering this and the increasing incidence of type 2 diabetes worldwide, the need for effective combination therapy is pressing. Basal insulin and glucagon-like peptide 1 (GLP-1) receptor agonists are frequently used to treat type 2 diabetes. Though both classes of medication are exclusively injectable, which may cause initial hesitation from providers, evidence for their combined use is substantial. This review summarizes the theoretical benefit, supporting evidence, and implementation of a combined basal insulin–GLP-1 receptor agonist regimen. Basal insulin added to a GLP-1 receptor agonist reduces hemoglobin A1c (HbA1c) without weight gain or significantly increased hypoglycemia. A GLP-1 receptor agonist added to basal insulin reduces HbA1c and body weight. Compared with the addition of meal-time insulin to basal insulin, a GLP-1 receptor agonist produces similar or greater reduction in HbA1c, weight loss instead of weight gain, and less hypoglycemia. Gastrointestinal adverse events are common with GLP-1 receptor agonists, especially during initiation and titration. However, combination with basal insulin is not expected to augment expected adverse events that come with using a GLP-1 receptor agonist. Basal insulin can be added to a GLP-1 receptor agonist with a slow titration to target goal fasting plasma glucose. In patients starting a GLP-1 receptor agonist, the dose of basal insulin should be decreased by 20 % in patients with an HbA1c ≤8 %. The evidence from 15 randomized prospective studies supports the combined use of a GLP-1 receptor agonist with basal insulin in a broad range of patients with uncontrolled type 2 diabetes.

Objective To evaluate trends in antibiotic resistance among Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa isolates submitted to the Antimicrobial Resistance Management (ARM) program between 1990 and 2002. Design The ongoing Antimicrobial Resistance Management (ARM) program is a queriable Web-based surveillance system that tracks resistance patterns among U.S. inpatient and outpatient isolates. This report represents data from 285 institutions and over 17 million isolates. Using a Web-based analysis tool, antibiogram and sensitivity reports of E. coli, K. pneumoniae, P. mirabilis, and P. aeruginosa isolates were reviewed for resistance to extended-spectrum cephalosporins and fluoroquinolones. Setting 285 teaching and non-teaching U.S Hospitals nationwide. Results For E. coli, resistance was 3.2% to ciprofloxacin (n = 444,947), 5.4% to levofloxacin (n = 201,532), and 0.8% to cefotaxime (n = 107,394), ceftriaxone (n = 464,931), and cefepime (n = 81,980), respectively. K. pneumoniae isolate resistance was 4.6% to ciprofloxacin (n = 144,698), 4.5% to levofloxacin (n = 57,462), 1.9% to cefotaxime (n = 33,189), 2.0% to ceftriaxone (n = 145,328) and 1.9% to cefepime (n = 25,503). For P. mirabilis, resistance was 12.5% to ciprofloxacin (n = 83,186), 12.2% to levofloxacin (n = 35,277), 1.0% to cefotaxime (n = 18,802), 0.7% to ceftriaxone (83,652), and 2.3% to cefepime (n = 13,968). P. aeruginosa resistance was also higher for fluoroquinolones (only 65.2% of isolates were susceptible to ciprofloxacin) compared to extended-spectrum cephalosporins, with ceftazidime exhibiting the greatest antipseudomonal activity. Clinically significant regional variations in the activity of fluoroquinolones and cephalosporins were apparent. Conclusion Resistance to the fluoroquinolones is increasing dramatically, whereas the third generation cephalosporins remain inherently more active. P. aeruginosa exhibits the most formidable resistance pattern with neither the antipseudomonal cephalosporins nor fluoroquinolones representing acceptable monotherapy options. Given the association between fluoroquinolone resistance and extended-spectrum β-lactamase production, continued surveillance is vital to preserve the activity of existing therapies.

Background: Staphylococcus aureus is a frequent cause of infections involving the bloodstream, skin and soft tissue, and lungs in hospitalized patients. These isolates are often multidrug resistant and represent a major therapeutic challenge. Objective: To explore the susceptibilities of S. aureus to nafcillin/oxacillin, a surrogate for methicillin resistance, and the fluoroquinolones and determine whether a relationship might exist between fluoroquinolone use and the prevalence of methicillin-resistant S. aureus (MRSA). Methods: To date, 353 institutions throughout the US and Puerto Rico have enrolled in the Antimicrobial Resistance Management (ARM) Program, and data have been submitted on nearly 5 million isolates of S. aureus. Isolates submitted from 1990 through 2002 were reviewed for sensitivity to nafcillin/oxacillin, clindamycin, erythromycin, and the fluoroquinolones ciprofloxacin and levofloxacin. Results: From 1990 through 2002 inclusive, susceptibility to nafcillin/oxacillin nationally was 64.9% (n = 360,460), ranging from 62.2% in the North Central and Northeast US to 72.8% in the Southwest. Nationally, S. aureus isolates were more resistant to levofloxacin (41.4%, n = 123,868) than ciprofloxacin (38.7%, n = 256,178). The greatest change in susceptibility of S. aureus to nafcillin/oxacillin and ciprofloxacin occurred concurrently from 1998 to 2002, which may implicate fluoroquinolone use with increasing rates of MRSA infection. Conclusions: Resistance to methicillin and the fluoroquinolones has increased in concert during the past 5 years. Collectively, data from the ARM Program, along with several other investigations, support a role of fluoroquinolone use in the emergence of MRSA. These observations, along with increasing resistance among gram-positive and gram-negative pathogens, underscore the need for judicious use of fluoroquinolones.

From a patient's perspective, stroke is the most devastating form of cardiovascular disease, representing the number one cause of permanent disability in the United States. Treatment of hypertension significantly reduces the risk of stroke; however, it is unclear whether all antihypertensive agents are equivalent in this regard. Angiotensin-converting enzyme (ACE) inhibitors have been shown to reduce the risk of cardiovascular events, including stroke. Although attenuation of the renin-angiotensin system (RAS) is often credited with the blood pressure-independent effects of this class of agents, this hypothesis has not been confirmed with regard to the end point of stroke. In fact, drugs that activate the RAS, such as diuretics and dihydropyridine calcium channel blockers, are as effective or superior to ACE inhibitors for stroke prevention. Angiotensin II receptor blockers (ARBs) selectively block the angiotensin II subtype I receptor, which results in a reflexive increase in levels of angiotensin II and unopposed activation of angiotensin II subtype 2 receptors. Clinical trials comparing ARBs with active controls have reported significant reductions in stroke in ARB-treated patients. Data on ARBs and other drugs that activate the RAS (diuretics and dihydropyridine calcium channel blockers) support a potential role for the RAS in protecting against stroke. Ongoing trials with ARBs are evaluating stroke as a primary end point, and results should help to further elucidate the role of ARBs in this disease. Until then, it is prudent to treat hypertension with an agent or combination of agents that are likely to result in a rapid and sustained reduction in blood pressure, taking into consideration patient characteristics, comorbidities, tolerability, and cost.

Purpose This update from the Antimicrobial Resistance Management (ARM) Program reports surveillance data for Streptrococcus pneumoniae and Haemophilus influenzae isolates from 1994 to 2002. Methods Antibiograms and sensitivity reports submitted to the ARM program database were reviewed for resistance to commonly prescribed antibiotics Results Nationally S. pneumoniae resistance to penicillin was 37.4% (n = 37,688); to erythromycin, 29.6% (n = 18,774); and to clindamycin, 9.9% (n = 5510). Resistance to cefotaxime was 25.5% (n = 10,527) and 16.8% to ceftriaxone (26,594). For H. influenzae, resistance to cefotaxime was 4.3% (n = 4,927) and to ceftriaxone 1% (n = 10,353), a difference seen largely in the Northeast. Conclusions Resistance to penicillin appears to have reached a plateau above 40%; however, sparing of beta-lactam antibiotics may occur at the expense of other agents (ie, macrolides). Clindamycin remains active against penicillin-resistant S. pneumoniae (PRSP), but use of agents with antianaerobic properties is discouraged. The ARM program suggests important differences between cefotaxime and ceftriaxone.

OBJECTIVE To describe the mutant selection window, discuss supporting evidence and limitations, and suggest potential applications for clinical practice. DATA SOURCES A MEDLINE search (1990–December 2003) of the English-language literature was conducted using the key words antibiotic, antimicrobial, resistance, mutant, selection window, prevention, MPC, and MSW in various combinations. Original investigations and reviews evaluating the mutant selection window, including abstracts and proceedings, were considered for inclusion. Published articles were also cross-referenced, and experts were contacted to locate additional pertinent data. STUDY SELECTION AND DATA EXTRACTION All data sources identified were evaluated and all information deemed relevant was included. DATA SYNTHESIS Until recently, physicians have had few ways to preserve antimicrobials from resistance other than by prescribing the agents less often. The mutant selection window hypothesis may modify this paradigm by shifting the focus to dosing strategies that reduce the growth of resistant mutants. Conventional dosing strategies have been formulated on the likelihood of curing an individual patient. Unfortunately, doses that cure patients appear to enrich resistant subpopulations of bacteria, thus promoting resistance. Antimicrobial—pathogen combinations can be identified that minimize mutant selection and cure patients while possibly restricting the progression of resistance. CONCLUSIONS The mutant selection window hypothesis provides a framework for considering the contribution of dosing to resistance, and it offers ideas for restricting the enrichment of resistant mutants and antimicrobial resistance.

PURPOSE: The physiological role and metabolism of magnesium, the causes of magnesium deficiency, clinical data on the benefits of magnesium supplementation, and the management of magnesium deficiency are discussed. SUMMARY: Magnesium is an often overlooked electrolyte that is essential to life. Magnesium plays a role in more than 300 enzymatic reactions and is critically involved in energy metabolism, glucose utilization, protein synthesis, fatty acid synthesis and breakdown, ATPase functions, and virtually all hormonal reactions. Magnesium is closely involved in maintaining cellular ionic balance through its association with sodium, potassium, and calcium. Deficiency of magnesium is becoming more common in the U.S. population and may be attributed to decreased dietary consumption and the use of diuretics; in the elderly, magnesium deficiency may be a consequence of reduced appetite, decreased mitochondrial respiratory activity, and increased myocardial collagen. Conditions that may be associated with magnesium deficiency include hypertension, congestive heart failure, arrhythmia, myocardial infarction, diabetes mellitus, and preeclampsia; in many of these, magnesium supplementation has been found beneficial in clinical studies. Supplementation should be considered for patients with risk factors for deficiency and should be instituted for patients showing symptoms of deficiency. In addition to instituting supplementation when appropriate, the clinician should identify and correct the underlying cause of the deficiency. CONCLUSION: Magnesium deficiency may contribute to pathological processes. Clinicians should consider using magnesium supplementation to prevent deficiency in patients at risk and to treat deficiency when it occurs.

OBJECTIVE: To provide pharmacists and other healthcare providers with a better understanding of new monitoring technologies for asthma and chronic obstructive pulmonary disease (COPD) available to clinics and pharmacies. DATA SOURCES: Forty scientific articles were identified through a MEDLINE search (1990–June 2003), additional references listed in articles, and abstracts from scientific meetings. STUDY SELECTION AND DATA EXTRACTION: English-language literature of controlled human clinical studies was reviewed to evaluate the accuracy, reliability, validity, and response of the new monitoring technologies. DATA SYNTHESIS: The In-Check DIAL is a pulmonary airflow meter that identifies the most appropriate inhaler for a patient and is useful in determining how efficiently patients use their inhalers. Electronic peak flow meters such as the AirWatch, VMX Wright Mini-Log, PiKo-1, and electronic asthma monitor store and download multiple pulmonary function test (PFT) readings to a personal computer, allowing easy identification of patients who are fabricating results. The AirWatch also has the ability to measure forced expiratory volume in 1 second. The Spirophone AG-SP, VM Plus, and Micro DiaryCard spirometer are portable spirometers that can be used at home without the need for supervision. Bronchial challenge tests have been recently standardized and may prove to be beneficial in modifying drug therapy in patients with asthma and COPD. CONCLUSIONS: Despite recent advances in medical technology, monitoring of asthma and COPD has not changed significantly. PFTs continue to be the gold standard for evaluating airway obstruction and/or restriction. Clinical trials that will evaluate outcomes such as decreased number of hospitalizations, emergency department visits, unscheduled visits to physicians, and days absent from school or work are needed to determine the utility of new monitoring technologies.

The spread of resistance to many antimicrobial agents in various microbial species has been highlighted by the World Health Organisation and many government agencies around the world. The reasons for this increase and spread are complex and are discussed. A number of surveillance studies has monitored the increase in resistance among isolates of Streptococcus pneumoniae to various important classes of antimicrobials. These results are discussed with particular reference to penicillins, macrolides and fluoroquinolones. Although there is evidence that in vitro resistance to macrolides and more recently to fluoroquinolones may be associated with a reduced clinical efficacy, there is no such clear association with resistance to beta-lactams and lack of clinical efficacy in non-meningeal infections. Resistance or susceptibility to an antimicrobial agent is based on breakpoints and these are set in the US by the National Committee of Clinical and Laboratory Standards. In response to these recent clinical studies showing that non-meningeal pneumococcal infections with strains classified as resistant in vitro still responded well to treatment with various beta-lactams, new breakpoints have been set. Results are presented showing that using these breakpoints, the levels of resistance to the third generation cephalosporins, ceftriaxone and cefotaxime against a range of non-meningeal pneumococcal isolates were lower than those obtained using the previous breakpoints. The excellent pharmacokinetic and pharmacodynamic properties of these agents are believed to contribute to their good activity in the clinic.

Hypokalemia is a recognized adverse effect of thiazide diuretic treatment. This phenomenon, which may impair insulin secretion, has been suggested to be a reason for the adverse effects on glucose metabolism associated with thiazide diuretic treatment of hypertension. However, the mechanisms underlying thiazide diuretic-induced hypokalemia are not well understood. In an effort to identify genes or genomic regions associated with potassium response to hydrochlorothiazide, without a priori knowledge of biologic effects, we performed a genome-wide association study and a multiethnic meta-analysis in 718 European- and African-American hypertensive participants from two different pharmacogenetic studies. Single-nucleotide polymorphisms rs10845697 (Bayes factor=5.560) on chromosome 12, near to the HEME binding protein 1 gene, and rs11135740 (Bayes factor=5.258) on chromosome 8, near to the Mitoferrin-1 gene, reached genome-wide association study significance (Bayes factor >5). These results, if replicated, suggest a novel mechanism involving effects of genes in the HEME pathway influencing hydrochlorothiazide-induced renal potassium loss.

To assess the relationship of the 33 single nucleotide polymorphisms (SNPs) previously associated with fasting glucose in Caucasians in genome-wide association studies (GWAS) with glucose response to antihypertensive drugs shown to increase risk for hyperglycemia and diabetes.Randomized, multicenter clinical trial.A total of 456 Caucasian men and women with uncomplicated hypertension.The Pharmacogenomic Evaluation of Antihypertensives Responses study evaluated blood pressure and glucose response in uncomplicated hypertensive patients randomized to either atenolol or hydrochlorothiazide (HCTZ) monotherapy, followed by combination therapy with both agents. Association of these SNPs with atenolol- or HCTZ-induced glucose response was evaluated in 456 Caucasian patients using linear regression adjusting for age, sex, body mass index, baseline glucose, baseline insulin, and principal component for ancestry. The SNP rs340874 in the 5' region of PROX1 gene was significantly associated with atenolol-induced glucose change (p=0.0013). Participants harboring the C allele of this SNP had greater glucose elevation after approximately 9 weeks of atenolol monotherapy (β = +2.39 mg/dl per C allele), consistent with the direction of effect in fasting glucose GWAS, that showed the C allele is associated with higher fasting glucose.These data suggest that PROX1 SNP rs340874, discovered in fasting glucose GWAS, may also be a pharmacogenetic risk factor for antihypertensive-induced hyperglycemia. β-blockers and thiazides may interact with genetic risk factors to increase risk for dysglycemia and diabetes.

Our aim was to identify financial and outcome benefits of therapeutic intervention by a multidisciplinary antimicrobial treatment team composed of pharmacists, a clinical microbiologist, and an infectious disease specialist. Of 252 consecutive inpatients receiving suboptimal intravenous antibiotics identified by the clinical pharmacist, 127 were prospectively randomized to intervention and 125 to a control group. The groups were similar with regard to severity of illness, infection type, and time from admission to randomization. Physicians received timely, detailed reviews of relevant microbiologic and clinical data with recommendations of possible optimal antibiotic choices, dosages, and rationales. Median length of stay after randomization for control and intervention groups was 9.0 days and 5.7 days, respectively (3.3-day difference, p=0.0001). Fifteen (12.0%) and eight patients (6.3%), respectively, died, although the time-specific mortality risk was not significantly different when length of postrandomization follow-up and time to death were taken into account. Physician acceptance of suggestions was 89%. Median patient charges for radiology, laboratory, pharmacy, and room were reduced by $4404/intervention, and median hospital costs were reduced by $2642/intervention. A multidisciplinary antimicrobial therapy team can be a useful information source for physicians, improve outcomes in hospitalized patients receiving intravenous antimicrobials, and result in substantial cost savings.

Hypertension, in spite of a very high prevalence, remains undertreated. This is not due to a lack of effective therapeutic modalities. Non-pharmacological treatments can be effective in many patients. If those treatments fail to reduce blood pressure sufficiently, the physician can choose between numerous classes of antihypertensive agents. However, interpatient variability in response to these agents is high, and use of multiple agents is frequently necessary. Thus, no single class has proven to be superior for the majority of patients. This article will review the different non-pharmacological and pharmacological methods available to treat hypertension, as well as the guidelines that are available to aid in proper selection of a treatment regimen.