John G. Gums

Pharmacogenomics of antihypertensive drugs : Rationale and design of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study

BACKGROUND Selection of antihypertensive therapy is often empiric, and use of genetic information to guide drug therapy selection holds future promise. TRIAL DESIGN The objective of this trial is to identify the genetic determinants of the antihypertensive and adverse metabolic responses to a thiazide diuretic (hydrochlorothiazide), a beta-blocker (atenolol), and their combination. This will be accomplished through candidate gene and genome-wide association approaches. Individuals with uncomplicated hypertension (N = 800), with ages 17 and 65 years, are being enrolled. Current antihypertensive therapy is discontinued, and hypertension is confirmed, along with collection of other baseline data. Subjects are then randomized to either hydrochlorothiazide or atenolol, with 1 dose titration step, followed by assessment of response to therapy after at least 6 weeks on the target dose. Those with blood pressure >120/70 mm Hg have the second drug added, with similar dose titration and response assessment procedures. Data collected include home, office, and 24-hour ambulatory blood pressure. Biological samples collected in the fasting state include plasma, serum, DNA (buffy coat), and urine. Epstein-Barr virus transformed lymphocyte cell lines are also being created. CONCLUSIONS Pharmacogenetic-guided therapy holds clinical potential for hypertension, but the literature in the field is limited. This trial will add substantially to our understanding of the genetic determinants of antihypertensive and adverse metabolic responses to 2 commonly used antihypertensive drug classes.

A randomized, prospective study measuring outcomes after antibiotic therapy intervention by a multidisciplinary consult team.

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

Plasma Renin Activity Predicts Blood Pressure Responses to β-Blocker and Thiazide Diuretic as Monotherapy and Add-On Therapy for Hypertension

4404/intervention, and median hospital costs were reduced by

Genomic Association Analysis of Common Variants Influencing Antihypertensive Response to Hydrochlorothiazide

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.

Impact of Abdominal Obesity on Incidence of Adverse Metabolic Effects Associated With Antihypertensive Medications

BACKGROUND Age and race categories or renin profiling have been recommended to predict blood pressure responses to monotherapy with a beta-blocker or thiazide diuretic. Whether these or other characteristics predict blood pressure responses when the drugs are administered as add-on therapy is uncertain. METHODS We evaluated predictors of blood pressure response in 363 men and women < or =65 years of age with primary hypertension (152 blacks, 211 whites), 86 of whom (24%) were untreated and 277 of whom (76%) were withdrawn from previous antihypertensive drugs before randomization to either atenolol followed by addition of hydrochlorothiazide (N = 180) or hydrochlorothiazide followed by addition of atenolol (N = 183). Responses were determined by home blood pressure averages before and after each drug administration. Race, age, plasma renin activity, and other characteristics including pretreatment blood pressure levels were incorporated into linear regression models to quantify their contributions to prediction of blood pressure responses. RESULTS Plasma renin activity and pretreatment blood pressure level consistently contributed to prediction of systolic and diastolic responses to each drug administered as mono- and as add-on therapy. Higher plasma renin activity was consistently associated with greater blood pressure responses to atenolol and lesser responses to hydrochlorothiazide. The predictive effects of plasma renin activity were statistically independent of race, age, and other characteristics. CONCLUSIONS Plasma renin activity and pretreatment blood pressure level predict blood pressure responses to atenolol and hydrochlorothiazide administered as mono- and as add-on therapy in men and women < or =65 years of age.

Polymorphisms in genes coding for GRK2 and GRK5 and response differences in antihypertensive-treated patients

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<10–5 were tested for replication of the associations in independent samples of hydrochlorothiazide-treated European hypertensives. The rs16960228 polymorphism in protein kinase C, &agr; 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.

Ceftobiprole: An Extended-Spectrum Anti–Methicillin-Resistant Staphylococcus aureus Cephalosporin

We assessed adverse metabolic effects of atenolol and hydrochlorothiazide among hypertensive patients with and without abdominal obesity using data from a randomized, open-label study of hypertensive patients without evidence of cardiovascular disease or diabetes mellitus. Intervention included randomization to 25 mg of hydrochlorothiazide or 100 mg of atenolol monotherapy followed by their combination. Fasting glucose, insulin, triglycerides, high-density lipoprotein cholesterol, and uric acid levels were measured at baseline and after monotherapy and combination therapy. Outcomes included new occurrence of and predictors for new cases of glucose ≥100 mg/dL (impaired fasting glucose), triglyceride ≥150 mg/dL, high-density lipoprotein ≤40 mg/dL for men or ≤50 mg/dL for women, or new-onset diabetes mellitus according to the presence or absence of abdominal obesity. Abdominal obesity was present in 167 (58%) of 395 patients. Regardless of strategy, in those with abdominal obesity, 20% had impaired fasting glucose at baseline compared with 40% at the end of study (P<0.0001). Proportion with triglycerides ≥150 mg/dL increased from 33% at baseline to 46% at the end of study (P<0.01). New-onset diabetes mellitus occurred in 13 patients (6%) with and in 4 patients (2%) without abdominal obesity. Baseline levels of glucose, triglyceride, and high-density lipoprotein predicted adverse outcomes, and predictors for new-onset diabetes mellitus after monotherapy in those with abdominal obesity included hydrochlorothiazide strategy (odds ratio: 46.91 [95% CI: 2.55 to 862.40]), female sex (odds ratio: 31.37 [95% CI: 2.10 to 468.99]), and uric acid (odds ratio: 3.19 [95% CI: 1.35 to 7.52]). Development of adverse metabolic effect, including new-onset diabetes mellitus associated with short-term exposure to hydrochlorothiazide and atenolol was more common in those with abdominal obesity.

Angiotensin Receptor Blockers versus ACE Inhibitors: Prevention of Death and Myocardial Infarction in High-Risk Populations

Objectives The G-protein-coupled receptor kinases (GRKs) GRK2 and GRK5 are important regulators of &bgr;-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. Methods 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. Results 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 G>A) 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]. Conclusion The GRK5 Leu41 allele protects from adverse cardiovascular outcomes in treated hypertensives.

Relief of Fibromyalgia Symptoms following Discontinuation of Dietary Excitotoxins

Objective: To summarize and evaluate the literature concerning ceftobiprole. Data Sources: Literature identification was conducted through MEDLINE (1966–February 2008) and International Pharmaceutical Abstracts (1970–February 2008) using the terms ceftobiprole, medocaril, BAL 5788, RO-5788, BAL 9141, RO 63-9141, pynolidinone cephalosporin. MRSA, complicated skin and skin-structure infections (cSSSIs), community-acquired pneumonia, and nosocomial pneumonia. Additional publications were identified through a review of articles and abstracts from infectious disease meetings. Study Selection and Data Extraction: All articles in English were evaluated and all pertinent information was included. Data Synthesis: Ceftobiprole medocaril is an extended-spectrum cephalosporin with activity against methicillin-reslstant Staphylococcus spp., vancomycin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant Enterococcus faecalis, Enterobacteriaceae, and Pseudomonas aeruginosa. Inactivity includes extended-spectrum β-lactamase (ESBL)–producing Enterobacteriaceae and Enterococcus faecium. Preliminary data suggest that ceftobiprole may be effective with a 1-hour infusion of 500 mg every 12 hours for gram-positive infections and 500 mg every 8 hours with a 2-hour infusion for polymicrobial infections. Two clinical trials support these dosing regimens for cSSSIs. Ceftobiprole was noninferior to vancomycin in suspected gram-positive cSSSIs, with cure rates of 93.3% and 93.5%, respectively. Furthermore, ceftobiprole was noninferior to vancomycin and ceftazidime in polymicrobial cSSSIs (cure rates 90.5% vs 90.2%, respectively). Although the total number of adverse effects was similar to those of the comparator, more patients in the ceftobiprole group experienced nausea, vomiting, and dysgeusia. Conclusions: The activity of ceftobiprole and limited clinical data suggest that it may be useful as empiric monotherapy for cSSSI and in combination with other antimicrobials in lower respiratory tract infections for which Phase 3 clinical trials are currently exploring. Although not shown in vitro, ceftobiprole may induce resistance due to its broad spectrum of activity. Approval is expected for the treatment of cSSSI.

Association of variants in NEDD4L with blood pressure response and adverse cardiovascular outcomes in hypertensive patients treated with thiazide diuretics

OBJECTIVE: To determine, through a review of the medical literature, whether there is adequate evidence to support the use of angiotensin receptor blockers (ARBs) in place of angiotensin-converting enzyme (ACE) inhibitors in high-risk populations, focusing on the prevention of death and myocardial infarction (MI). DATA SOURCES: Original investigations, reviews, and meta-analyses were identified from the biomedical literature via a MEDLINE search (1966–August 2004). Published articles were also cross-referenced for pertinent citations, and recent meeting abstracts were searched for relevant data. STUDY SELECTION AND DATA EXTRACTION: All articles identified during the search were evaluated. Preference was given to prospective, randomized, controlled trials that evaluated major cardiovascular endpoints and compared ARBs with ACE inhibitors, active controls, or placebo. DATA SYNTHESIS: The renin—angiotensin system plays a pivotal role in the continuum of cardiovascular disease and represents a major therapeutic target in the treatment of patients at risk for vascular events. While ACE inhibitors have been definitively shown to prevent death and MI, studies with ARBs in similar populations have not reduced these endpoints. In clinical trials that enrolled patients with heart failure, post-MI, diabetes, and hypertension, ARBs did not prevent MI or prolong survival compared with ACE inhibitors, other antihypertensives, or placebo. CONCLUSIONS: ACE inhibitors and ARBs should not be considered interchangeable, even among patients with a documented history of ACE inhibitor intolerance. ARBs can be considered a second-line alternative in such patients with the realization that they have not been shown to prevent MI or prolong survival.