Genome-wide association analysis of common genetic variants of resistant hypertension.

Resistant hypertension (RHTN), defined as uncontrolled blood pressure (BP) ≥ 140/90 using three or more drugs or controlled BP (<140/90) using four or more drugs, is associated with adverse outcomes, including decline in kidney function. We conducted a genome-wide association analysis in 1194 White and Hispanic participants with hypertension and coronary artery disease from the INternational VErapamil-SR Trandolapril STudy-GENEtic Substudy (INVEST-GENES). Top variants associated with RHTN at p < 10-4 were tested for replication in 585 White and Hispanic participants with hypertension and subcortical strokes from the Secondary Prevention of Subcortical Strokes GENEtic Substudy (SPS3-GENES). A genetic risk score for RHTN was created by summing the risk alleles of replicated RHTN signals. rs11749255 in MSX2 was associated with RHTN in INVEST (odds ratio (OR) (95% CI) = 1.50 (1.2-1.8), p = 7.3 × 10-5) and replicated in SPS3 (OR = 2.0 (1.4-2.8), p = 4.3 × 10-5), with genome-wide significance in meta-analysis (OR = 1.60 (1.3-1.9), p = 3.8 × 10-8). Other replicated signals were in IFLTD1 and PTPRD. IFLTD1 rs6487504 was associated with RHTN in INVEST (OR = 1.90 (1.4-2.5), p = 1.1 × 10-5) and SPS3 (OR = 1.70 (1.2-2.5), p = 4 × 10-3). PTPRD rs324498, a previously reported RHTN signal, was among the top signals in INVEST (OR = 1.60 (1.3-2.0), p = 3.4 × 10-5) and replicated in SPS3 (OR = 1.60 (1.1-2.4), one-sided p = 0.005). Participants with the highest number of risk alleles were at increased risk of RHTN compared to participants with a lower number (p-trend = 1.8 × 10-15). Overall, we identified and replicated associations with RHTN in the MSX2, IFLTD1, and PTPRD regions, and combined these associations to create a genetic risk score.

Pharmacogenetic Associations of ß1-Adrenergic Receptor Polymorphisms With Cardiovascular Outcomes in the SPS3 Trial (Secondary Prevention of Small Subcortical Strokes).

BACKGROUND AND PURPOSE: Functional polymorphisms (Ser49Gly and Arg389Gly) in ADRB1 have been associated with cardiovascular and ß-blocker response outcomes. Herein we examined associations of these polymorphisms with major adverse cardiovascular events (MACE), with and without stratification by ß-blocker treatment in patients with a history of stroke. METHODS: Nine hundred and twenty-six participants of the SPS3 trial's (Secondary Prevention of Small Subcortical Strokes) genetic substudy with hypertension were included. MACE included stroke, myocardial infarction, and all-cause death. Kaplan-Meier and multivariable Cox regression analyses were used. Because the primary component of MACE was ischemic stroke, we tested the association of Ser49Gly with ischemic stroke among 41 475 individuals of European and African ancestry in the NINDS (National Institute of Neurological Disorders and Stroke) SiGN (Stroke Genetics Network). RESULTS: MACE was higher in carriers of the Gly49 allele than in those with the Ser49Ser genotype (10.5% versus 5.4%, log-rank P=0.005). Gly49 carrier status was associated with MACE (hazard ratio, 1.62; 95% confidence interval, 1.00-2.68) and ischemic stroke (hazard ratio, 1.81; 95% confidence interval, 1.01-3.23) in SPS3 and with small artery ischemic stroke (odds ratio, 1.14; 95% confidence interval, 1.03-1.26) in SiGN. In SPS3, ß-blocker-treated Gly49 carriers had increased MACE versus non-ß-blocker-treated individuals and noncarriers (hazard ratio, 2.03; 95% confidence interval, 1.20-3.45). No associations were observed with the Arg389Gly polymorphism. CONCLUSION: Among individuals with previous small artery ischemic stroke, the ADRB1 Gly49 polymorphism was associated with MACE, particularly small artery ischemic stroke, a risk that may be increased among ß-blocker-treated individuals. Further research is needed to define ß-blocker benefit among ischemic stroke patients by ADRB1 genotype. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059306.

CYP2C19 metabolizer status and clopidogrel efficacy in the Secondary Prevention of Small Subcortical Strokes (SPS3) study.

BACKGROUND: The role of the CYP2C19 genotype on clopidogrel efficacy has been studied widely, with data suggesting reduced clopidogrel efficacy in loss-of-function variant carriers taking clopidogrel after percutaneous coronary intervention; however, data are limited regarding the association between CYP2C19 genetic variants and outcomes in stroke patients. We investigated whether CYP2C19 metabolizer status affects the risk of recurrent stroke or major bleeding in subcortical stroke patients taking dual antiplatelet therapy with aspirin and clopidogrel. METHODS AND RESULTS: CYP2C19*2 and CYP2C19*17 were genotyped in 522 patients treated with dual antiplatelet therapy from the Secondary Prevention of Small Subcortical Strokes (SPS3) study. CYP2C19 metabolizer status was inferred from genotype, and associations with the risk of recurrent stroke and major bleeding were assessed in the overall cohort and by race/ethnic group with logistic regression modeling. In the overall cohort, there were no differences in outcomes by CYP2C19 metabolizer status (recurrent stroke, odds ratio 1.81 [95% CI 0.76 to 4.30]; major bleeding, odds ratio 0.67 [95% CI 0.22 to 2.03]). In white participants, those with CYP2C19 intermediate or poor metabolizer status had higher odds of recurrent stroke (odds ratio 5.19 [95% CI 1.08 to 24.90]) than those with extensive or ultrarapid metabolizer status, but there was no evidence of difference in major bleeding. CONCLUSIONS: There were significant differences in recurrent stroke by CYP2C19 genotype-inferred metabolizer status in white subcortical stroke patients receiving dual antiplatelet therapy with aspirin and clopidogrel, consistent with cardiovascular studies on CYP2C19 and clopidogrel; however, the bleeding risk that led to early termination of the antiplatelet arm of the SPS3 trial does not appear to be explained by CYP2C19 genotype. This study was relatively underpowered; therefore, these findings should be interpreted with caution and warrant replication. CLINICAL TRIAL REGISTRATION: URL: www.clinicaltrials.gov. Unique identifier: NCT00059306.

Recurrence of prostate cancer in patients receiving testosterone supplementation for hypogonadism.

PURPOSE: The relationship between recurrent prostate cancer risk and testosterone replacement therapy (TRT) for hypogonadal men is explored. SUMMARY: The medical literature was searched to identify articles evaluating the use of TRT in symptomatic hypogonadal men with a history of prostate cancer. Eight English-language articles investigating TRT use in hypogonadal men with a history of prostate cancer were analyzed. For evaluative purposes, the normal ranges used for prostate-specific antigen (PSA) and total testosterone levels were less than 4.0 ng/mL and 300-1000 ng/dL, respectively. Most trials were small and involved patients with localized prostate cancer treated with radical prostatectomy or radiotherapy, though patients with metastatic disease or a Gleason score of ≥8 were included in a few studies. TRT was administered in a variety of dosages and dosage forms for up to nine years to manage hypogonadal symptoms. Testosterone concentrations increased, as expected, after TRT, but serum PSA levels remained below 0.1 ng/mL in the majority of patients. PSA levels were found to increase in select patients with high-risk and metastatic disease, but these elevations were not accompanied by disease progression. These studies have suggested a potential benefit for TRT use in select symptomatic hypogonadal men with a history of prostate cancer. Data were limited, however, by the retrospective nature of most studies, the lack of control groups, small sample sizes, and short follow-up periods. CONCLUSION: There is insufficient evidence to withhold TRT in certain populations of men with a history of prostate cancer.

ASA failure: does the combination ASA/clopidogrel confer better long-term vascular protection?

OBJECTIVE: To assess whether adding clopidogrel to acetylsalicylic acid (ASA) has a long-term protective vascular effect in patients with lacunar stroke while taking ASA. METHODS: Post hoc analysis of 838 patients with ASA failure and recent lacunar stroke from the Secondary Prevention of Small Subcortical Strokes Trial (SPS3) cohort randomly allocated to aspirin (325 mg/day) and clopidogrel (75 mg/day) or placebo. Primary efficacy outcome was stroke recurrence (ischemic and intracranial hemorrhage) and main safety outcome was major extracranial hemorrhage. Patients were followed for a mean period of 3.5 years. RESULTS: The ASA failure group had a significantly higher risk of vascular events including ischemic stroke when compared with the non-ASA failure group (n = 2,151) in SPS3 (p = 0.03). Mean age was 65.6 years and 65% were men. The risk of recurrent stroke was not reduced in the dual antiplatelet group, 3.1% per year, compared to the aspirin-only group, 3.3% per year (hazard ratio [HR] 0.91; 95% confidence interval [CI] 0.61-1.37). There was also no difference between groups for ischemic stroke (HR 0.90; 95% CI 0.59-1.38). The risk of gastrointestinal bleeding was higher in the dual antiplatelet group (HR 2.7; 95% CI 1.1-6.9); however, the risk of intracranial hemorrhage was not different. CONCLUSIONS: In patients with a recent lacunar stroke while taking ASA, the addition of clopidogrel did not result in reduction of vascular events vs continuing ASA only. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with recent lacunar stroke while taking ASA, adding clopidogrel as compared to continuing ASA alone does not reduce the risk of recurrent stroke.

Predictors of stroke recurrence in patients with recent lacunar stroke and response to interventions according to risk status: secondary prevention of small subcortical strokes trial.

BACKGROUND: Among participants in the Secondary Prevention of Small Subcortical Strokes randomized trial, we sought to identify patients with high versus low rates of recurrent ischemic stroke and to assess effects of aggressive blood pressure control and dual antiplatelet therapy according to risk status. METHODS: Multivariable analyses of 3020 participants with recent magnetic resonance imaging-defined lacunar strokes followed for a mean of 3.7 years with 243 recurrent ischemic strokes. RESULTS: Prior symptomatic lacunar stroke or transient ischemic attack (TIA) (hazard ratio [HR] 2.2, 95% confidence interval [CI] 1.6, 2.9), diabetes (HR 2.0, 95% CI 1.5, 2.5), black race (HR 1.7, 95% CI 1.3, 2.3), and male sex (HR 1.5, 95% CI 1.1, 1.9) were each independently predictive of recurrent ischemic stroke. Recurrent ischemic stroke occurred at a rate of 4.3% per year (95% CI 3.4, 5.5) in patients with prior symptomatic lacunar stroke or TIA (15% of the cohort), 3.1% per year (95% CI 2.6, 3.9) in those with more than 1 of the other 3 risk factors (27% of the cohort), and 1.3% per year (95% CI 1.0, 1.7) in those with 0-1 risk factors (58% of the cohort). There were no significant interactions between treatment effects and stroke risk status. CONCLUSIONS: In this large, carefully followed cohort of patients with recent lacunar stroke and aggressive blood pressure management, prior symptomatic lacunar ischemia, diabetes, black race, and male sex independently predicted ischemic stroke recurrence. The effects of blood pressure targets and dual antiplatelet therapy were similar across the spectrum of independent risk factors and recurrence risk.

Antibacterials as adjuncts to incision and drainage for adults with purulent methicillin-resistant Staphylococcus aureus (MRSA) skin infections.

The annual incidence of skin and soft tissue infections (SSTIs) has nearly tripled in the US since the early 1990s. Many purulent SSTIs in the community setting are caused by methicillin-resistant Staphylococcus aureus (MRSA). Incision and drainage (I&D) are indicated for most purulent MRSA infections; however, the use of adjunctive antibacterials is controversial. The objective of this study was to systematically evaluate studies that have investigated whether or not antibacterials provide added benefit to I&D alone for purulent MRSA SSTIs. We included articles from MEDLINE and The Cochrane Library that fulfilled the following criteria: (i) original research; (ii) English language; (iii) compared I&D alone versus I&D plus antibacterials for purulent MRSA SSTIs; and (iv) compared patient outcomes. We also reviewed the references of these articles to identify other relevant studies. Studies that solely examined paediatric patients were excluded. To facilitate cross-study comparison, we systematically evaluated the following study characteristics: (i) study design; (ii) patient population; (iii) comparator groups; (iv) sample size; (v) outcome measures; (vi) outcome definitions; (vii) duration of follow-up; and (viii) measurement and adjustment of potential confounding variables. Eleven studies, spanning more than 30 years, met inclusion criteria. Two of these were conducted prior to the emergence of MRSA in the community; another evaluated cephalexin versus placebo for MRSA. None of these found added benefit of adjunctive antibacterials. Four studies compared health outcomes between patients who received 'active' or 'appropriate' therapy and those who received 'inactive' or 'inappropriate' therapy after I&D for purulent MRSA SSTIs. Two of these studies found 'active' or 'appropriate' therapy to be beneficial, while two others did not. Four studies compared health outcomes between patients who received anti-MRSA antibacterials plus I&D with those who received alternative antibacterials plus I&D for purulent MRSA SSTIs. Three of these reported improved outcomes with anti-MRSA antibacterials, while another reported mixed findings. Presently, the bulk of the available evidence suggests anti-MRSA antibacterials provide added benefit to I&D alone for purulent MRSA SSTIs; however, the current evidence is limited to small, case-control, observational studies.

The Hispanic Diabetes Management Program: Impact of community pharmacists on clinical outcomes.

OBJECTIVE: To assess the impact of community pharmacists on clinical outcomes in Hispanic patients with type 2 diabetes. METHODS: 126 patients were enrolled in this longitudinal pre/post cohort study that took place in nine community and four workplace pharmacies in San Antonio, TX. Pharmacists provided education, point-of-care testing for glycemic and metabolic parameters, clinical assessment, goal setting, and drug therapy management with physicians. Study outcomes were changes in glycosylated hemoglobin (A1C) and accompanying metabolic parameters (blood pressure, lipid parameters, and body mass index) during a 1-year time frame. RESULTS: In the overall cohort, A1C was not reduced significantly from baseline to 12 months (7.8% vs. 7.6%, P = 0.516). However, statistically significant reductions occurred for fasting plasma glucose, triglycerides, and diastolic blood pressure. None of the other parameters was affected significantly. In the subgroup of patients not at target values at baseline, significant reductions occurred for A1C (9.2% vs. 8.6%, P = 0.001), systolic blood pressure (147 vs. 143 mm Hg, P = 0.031), diastolic blood pressure (91 vs. 87 mm Hg, P < 0.001), triglycerides (259 vs. 219 mg/dL, P < 0.001), LDL cholesterol (139 vs. 123 mg/dL, P < 0.001), and total cholesterol (237 vs. 222 mg/dL, P = 0.008). CONCLUSION: Interventions performed by community pharmacists are effective in improving clinical outcomes in a Hispanic cohort with diabetes. Pharmacists' efforts were most successful in patients not at target glycemic and metabolic levels.

Pravastatin versus simvastatin for prevention of contrast-induced nephropathy.

Contrast-induced nephropathy (CIN) is associated with long-term morbidity, mortality, and increased health care costs. It has been suggested that statins have pleiotropic effects countering inflammatory and oxidative stress involved in CIN. Several studies support this theory; however, previously published studies have not evaluated the potential differences between statins in reducing the incidence of CIN. The purpose of this retrospective, single-center trial was to compare the incidence of CIN in patients receiving simvastatin or pravastatin therapy undergoing percutaneous coronary intervention (PCI). A total of 261 patients were included (145 received simvastatin and 116 received pravastatin) with the majority undergoing elective PCI. The population was predominantly male (65%), Hispanic (65%), and diabetic (62%), with a mean age of 59 years and a low-density lipoprotein (LDL) of 85 mg/dL. No significant differences were found between groups for risk factors or prophylactic strategies (eg, hydration). Contrast-induced nephropathy occurred in 26 patients (17.9%) in the simvastatin group versus 10 (8.6%) in the pravastatin group (P < .05). No patients required dialysis as a result of contrast administration. Acute kidney injury (AKI) occurred in 21 patients (14.5%) in the simvastatin group compared to 8 (6.9%) in the pravastatin group (P < .05). In multivariate analysis, the difference between statins remained an independent predictor for the development of CIN. In conclusion, patients on pravastatin had a significantly lower incidence of CIN compared to patients on simvastatin.

Preclinical evaluation of tacrolimus colloidal dispersion for inhalation.

Substantial improvements in transplant therapy have been made in the past four decades resulting in the acceptance of organ transplantation as a viable treatment for late-stage disease and organ failure. More recently, lung transplantation has gained acceptance; however, high incidence of chronic rejection and opportunistic infections has limited success rates in comparison with other transplant procedures. To achieve more targeted therapy, pulmonary administration of nebulized tacrolimus (TAC) colloidal dispersion once daily for 28 consecutive days in Sprague Dawley (SD) rats has been investigated for safety and systemic elimination. A liquid dispersion of colloidal TAC and lactose (1:1 ratio by weight) was aerosolized using a vibrating mesh nebulizer and administered via a nose-only dosing chamber. Blood chemistry and histological comparisons to saline-dosed animals showed no clinically significant differences in liver and kidney function or lung tissue damage. Maximum blood and lung concentrations sampled 1h after the final dose showed TAC concentrations of 10.1 ± 1.4 ng/mL and 1758.7 ± 80.0 ng/g, respectively. Twenty-four hours after the final dose, systemic TAC concentrations measured 1.0 ± 0.5 ng/mL, which is well below clinically accepted trough concentrations (5-15 ng/mL) for maintenance therapy, and therefore, would not be expected to induce toxic side effects. The propensity for pulmonary retention seen when compared to single dose lung levels may be due to macrophage uptake and the lipophilic nature of TAC. Additionally, three month stability testing of TAC powder for reconstitution showed no changes in amorphous nature or drug potency when stored at ambient conditions. TAC colloidal dispersion proved to be non-toxic when administered by pulmonary inhalation to SD rats over 28 days while providing therapeutic concentrations locally. This delivery strategy may prove safe and effective for the prevention of lung allograft rejection in lung transplant recipients.

Retrospective cohort study of hospitalized adults treated with vancomycin or clindamycin for methicillin-resistant Staphylococcus aureus skin infections.

BACKGROUND: Vancomycin alternatives, including clindamycin, have in vitro activity against current strains of methicillin-resistant Staphylococcus aureus (MRSA), but clinical evidence of their effectiveness is needed. OBJECTIVE: The aim of this work was to compare health outcomes for hospitalized adult patients treated with vancomycin and clindamycin for skin and soft- tissue infections caused by MRSA. METHODS: This was a retrospective chart review of patients admitted to University Hospital (San Antonio, Texas) with culture-proven MRSA skin or soft-tissue infections from July 1, 2006, to December 31, 2006. Patients were subdivided into groups according to antibiotics received on the first day of hospital admission. The primary outcome was composite failure, which was defined as having an additional positive MRSA culture 5 to 90 days after initial culture or requiring an additional intervention (eg, new course of antibiotics or additional incision and drainage within 90 days after initiation of therapy). Descriptive statistics were used to characterize each group; χ(2), Fisher exact, and Wilcoxon rank sum tests were used to assess differences between the vancomycin and clindamycin groups. RESULTS: Ninety-one patients received vancomycin (n = 40) or clindamycin (n = 51) for a MRSA skin infection. Most vancomycin-treated patients received 1 g IV q12h (92.5% [37/40]), whereas most clindamycintreated patients received 600 mg IV q8h (51.0% [26/51]) or 900 mg IV q8h (27.5% [14/51]). The vancomycin and clindamycin groups had no significant differences with regard to median age (38 vs 37 years, respectively), male sex (62.5% [25/40] vs 74.5% [38/51]), or Hispanic ethnicity (77.5% [31/40] vs 78.4% [40/51]). All MRSA isolates were susceptible to vancomycin and trimethoprimsulfamethoxazole. Few patients who received clindamycin were resistant to clindamycin (3.9% [2/51]). No patients died in the hospital. There were no significant differences between the vancomycin (n = 40) and clindamycin (n = 51) groups with respect to composite failure (15.0% [6/40] vs 7.8% [4/51], respectively), microbiologic failure (2.5% [1/40] vs 3.9% [2/51]), additional inpatient interventions (5.0% [2/40] vs 3.9% [2/51]), or additional outpatient interventions (12.5% [5/40] vs 3.9% [2/51]). Most patients (93.4% [85/91]) received incision and drainage. When those who did not were excluded from the analyses, all trends remained unchanged. CONCLUSIONS: In a single institution with a low rate of clindamycin resistance, there were no significant differences between vancomycin and clindamycin for the treatment of these hospitalized patients with MRSA skin infections, on the basis of clinical outcomes data. This finding warrants further investigation in a randomized controlled trial.

Trimethoprim-sulfamethoxazole or clindamycin for community-associated MRSA (CA-MRSA) skin infections.

BACKGROUND: In the United States, community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as the predominant cause of skin infections. Trimethoprim-sulfamethoxazole (TMP-SMX) and clindamycin are often used as first-line treatment options, but clinical data are lacking. METHODS: We conducted a retrospective cohort study of outpatients with skin and soft tissue infections managed from July 1 to December 31, 2006. Patients younger than 18 years of age were excluded, as were those who had no clinical admission or progress notes; were hospitalized within the 90 days before admission; were hospitalized with polymicrobial, surgical site, catheter-related, or diabetic foot infections; or were discharged to places other than home. Patient demographics, comorbidities, diagnoses, cultures, prescribed antibiotics, susceptibilities, surgical procedures, and health outcomes were extracted from electronic medical records. Patients were divided in 2 cohorts for further analysis: TMP-SMX and clindamycin. The primary study outcome was composite failure defined as an additional positive MRSA culture from any site 5 to 90 days after treatment initiation or an additional intervention during a subsequent outpatient or inpatient visit. Baseline characteristics and failure rates were compared using χ(2), Fisher's exact, and Wilcoxon rank sum tests. RESULTS: A total of 149 patients were included in this study. These patients had a median age of 36 years, 55% were men, 71% were Hispanic, 42% were uninsured, and 60% received an incision and drainage procedure. Patients who did not receive incision and drainage were twice as likely to experience the composite failure endpoint (57% vs 29%; P < .001). Failure rates were 25% for patients who received incision and drainage plus antibiotics compared with 60% for patients who received incision and drainage minus antibiotics (P = .03). When patients who did not receive incision and drainage were excluded, there were no significant differences between the TMP-SMX (n = 54) and clindamycin (n = 20) cohorts with respect to composite failures (26% vs 25%), microbiologic failures (13% vs 15%), additional inpatient interventions (6% vs 5%), or additional outpatient interventions (20% vs 20%). CONCLUSIONS: Our findings reinforce the belief that incision and drainage and antibiotics are critical for the management of CA-MRSA skin infections. Patients who receive TMP-SMX or clindamycin for their CA-MRSA skin infections experience similar rates of treatment failure.

Role of antihypertensive therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in combination with calcium channel blockers for stroke prevention.

OBJECTIVE: To review the available literature on the effects of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and calcium channel blockers (CCBs) or combinations of these agents on stroke outcomes in hypertensive patients. DATA SOURCES: A Medline search was conducted using the search terms stroke and antihypertensives, calcium channel blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers from 1985 to August 17, 2009. STUDY SELECTION: Randomized controlled clinical trials with at least 400 randomized patients were selected if at least one of the treatment arms used a CCB, ACEI, or ARB to evaluate stroke outcomes in hypertensive patients. DATA SYNTHESIS: The prevalence of stroke is high in the United States, accounting for approximately 150,000 deaths per year. Early identification and treatment of hypertension to quickly achieve blood pressure reduction is critical in the prevention of stroke. Many trials have provided evidence that CCBs, ACEIs, and ARBs are effective in stroke prevention. Most patients require two or more antihypertensive drugs to achieve blood pressure goals. Because of their complementary actions, combination antihypertensive therapy with a renin-angiotensin-aldosterone system (RAAS) blocker and a CCB may help reduce stroke incidence to a greater extent than either of the monotherapies. CONCLUSION: A growing body of clinical trial data suggest that aggressive combination antihypertensive therapy, including a RAAS blocker and CCB, may help reduce stroke incidence. Fixed-dose combination therapy is an important consideration in optimizing blood pressure control and patient adherence to therapy in stroke prevention.

Proton pump inhibitors and clopidogrel: is it a significant drug interaction?

IMPORTANCE OF THE FIELD: Clopidogrel is indicated as part of a dual antiplatelet therapy (DAT) with aspirin for the prevention of cardiac related events in acute coronary syndromes particularly in patients undergoing percutaneous coronary intervention. Recently, there have been reports of a clinically significant drug interaction between clopidogrel and proton pump inhibitors (PPI), which are frequently co-prescribed to prevent DAT associated gastrointestinal (GI) bleeding. AREAS COVERED IN THIS REVIEW: This review evaluates the risk of GI bleeding associated with DAT and the rationale for the use of PPI. This review also describes the pharmacokinetic and pharmacodynamic basis for the interaction and evaluates its significance on clinical outcomes. An extensive literature search on PubMed from January 1980 to August 2009 was performed. Additionally, abstracts and presentations from key cardiology meetings and press releases were reviewed for relevant studies related to the interaction. WHAT THE READER WILL GAIN: At the end of the review, readers should have a complete understanding of the interaction and steps that can be taken to limit the interaction. TAKE HOME MESSAGE: There is a mechanistic basis and pharmacodynamic data supporting an interaction between PPIs, particularly omeprazole and clopidogrel. The clinical significance of this interaction is, however, still a subject of intense debate and ongoing research.

Overview of advances in cardiovascular disease treatment and prevention: the evolving role of antiplatelet therapy.

PURPOSE: The role of antiplatelet therapy in preventing and treating cardiovascular disease is reviewed. SUMMARY: Cardiovascular disease, especially coronary heart disease, contributes to substantial morbidity and mortality in the United States and raises healthcare costs. Current guidelines from the American College of Cardiology and the American Heart Association, in conjunction with the Society for Cardiovascular Angiography and Interventions, recommend percutaneous coronary intervention (PCI) and stent placement to improve cardiovascular outcomes in patients with acute coronary syndrome, which encompasses unstable angina and myocardial infarction. Following stent placement, dual antiplatelet therapy with aspirin and a thienopyridine (clopidogrel or ticlopidine) significantly reduces the incidence of early major adverse cardiac events and mortality compared with aspirin alone or in combination with warfarin, and is the current standard of care for patients undergoing PCI. Maintenance therapy should be continued for at least one month after placement of a bare-metal stent, and at least three months or six months after placement of a sirolimus- or paclitaxel-eluting stent; ideally, therapy should be continued for one year following PCI. Even utilizing this standard, however, adverse clinical events do occur. In addition, treatment is often discontinued within the first year after stent placement by either the healthcare provider or the patient. CONCLUSION: Premature discontinuation of antiplatelet therapy is associated with an increased risk of adverse outcomes and can be avoided through better understanding of these risks by healthcare professionals and improved patient education.

Increases in SLT2 expression and chitin content are associated with incomplete killing of Candida glabrata by caspofungin.

Incomplete killing was observed for caspofungin against Candida glabrata, which was associated with increased SLT2 expression and elevated chitin content. In contrast, fungicidal activity and no chitin increase were observed in an isogenic Delta slt2 strain, suggesting a role for SLT2 and chitin production in the response of C. glabrata to caspofungin.

Targeting low HDL-cholesterol to decrease residual cardiovascular risk in the managed care setting.

BACKGROUND: Most clinicians recognize the importance of reducing low-density lipoprotein cholesterol (LDL-C) and, therefore, address this therapeutic need to decrease cardiovascular disease risk. In addition to the critical role that LDL-C plays, recent studies have shown the contribution of other lipid fractions, such as high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG), to overall cardiovascular health. Managed care initiatives to reduce cardiovascular risk typically focus on highly effective statin therapies, which are primarily LDL-C-lowering agents and have lesser TG-lowering and HDL-C-raising effects. However, clinical and epidemiologic data illustrate the need to expand the scope of therapies to reduce the residual cardiovascular risk associated with low HDL-C levels and elevated TG levels, even when LDL-C is managed successfully. OBJECTIVE: To address the value of treating beyond LDL-C level to improve patient health outcomes and reduce health care-related costs. SUMMARY: Several large trials and meta-analyses have investigated the effects of lipid-lowering statin therapy and have consistently demonstrated that statin therapy significantly reduces LDL-C levels and incidence of cardiovascular events. In spite of the efficacy of statin therapy in these studies, statins did not eliminate cardiovascular risk. Rather, significant residual cardiovascular risk remains after treatment with statins, especially in high-risk patients such as those with diabetes. Residual cardiovascular risk stems, at least partially, from low HDL-C and elevated TG. Low HDL-C levels have been identified as a significant, independent predictor of cardiovascular risk, and increases in HDL-C are associated with reductions in cardiovascular events. High TG levels are a significant risk factor for cardiovascular disease and are a marker for atherogenic remnant lipo-proteins, such as very low-density lipoprotein cholesterol (VLDL-C). Additionally, with elevated TG levels, a combination of LDL-C with VLDL-C in the measure of non-HDL-C may be a better predictor of cardiovascular risk than LDL-C alone. Recent national treatment guidelines suggest that combination therapy may be necessary to address multiple lipid targets (i.e., LDL-C, non-HDL-C, HDL-C, and TG); adding niacin or a fibrate to a statin is a therapeutic option that should be considered. As monotherapy agents, fibrates and niacin have been demonstrated to alter several lipid parameters and reduce cardiovascular events. Niacin appears to exert the greatest beneficial effects on the widest range of lipoprotein abnormalities, in addition to possessing an established safety profile. Moreover, niacin/statin combination therapy may provide greater benefits, as manifested through a correction of atherogenic lipid abnormalities, a slowing of atherosclerosis progression in coronary heart disease (CHD) patients, and a reduction of residual cardiovascular risk. Pharmacoeconomic modeling studies have been used to describe the potential effects on both cardiovascular events and health care costs by the achievement of, or failure to achieve, combined optimal lipid values (OLVs). Achievement of OLVs is predicted to be associated with a reduced risk of cardiovascular events, in which greater magnitudes of risk reduction accompany the achievement of a greater number of lipid goals. Based on patient baseline lipid values and product labeling information, mathematical models estimate that OLVs are achieved more frequently with extended-release niacin (niacin ER)/simvastatin combination therapy than with other high-potency agents. These modeling estimates were maintained in different patient groups, including those with diabetes or the metabolic syndrome. Finally, these modeling studies estimated that a fixed-dose niacin ER/simvastatin combination therapy would reduce direct medical costs of CHD events more effectively than would high-dose simvastatin monotherapy. CONCLUSION: Statins are highly effective for lowering LDL-C levels and, consequently, cardiovascular event rates. However, statins do not eliminate cardiovascular risk. Even in the presence of tightly controlled LDL-C levels, evidence indicates that high TG and low HDL-C levels are independent cardiovascular risk factors. Treating lipid parameters beyond LDL-C may require the addition of niacin or a fibrate to statin therapy. Niacin is the most effective agent for raising HDL-C levels, and pharmacoeconomic modeling suggests that niacin ER/statin combination therapy may promote the cost-effective achievement of OLVs in several at-risk patient populations.

Topical verapamil HCl, topical trifluoperazine, and topical magnesium sulfate for the treatment of Peyronie's disease--a placebo-controlled pilot study.

INTRODUCTION: Transdermal and intralesional verapamil has been reported to be useful in the treatment of Peyronie's Disease. This study evaluates a topically applied calcium channel blocker (verapamil hydrochloride 15% gel), a topically applied calmodulin blocker (trifluoperazine), and a topically applied weak calcium channel blocker (magnesium sulfate), each incorporated in a transdermal vehicle. AIM: This pilot study was conducted to assess the efficacy of a 15% verapamil gel applied topically to the penile shaft twice daily for the treatment of Peyronie's Disease. MAIN OUTCOME MEASURE: To assess improvement in curvature, plaque size, resolution of painful erections, and improvement in erection quality. METHODS: Two simultaneous, three armed, double blinded, placebo-controlled studies were conducted. After randomization into one of four groups, patients were treated for 3 months. At the end of 3 months' treatment using blinded drug, each patient was treated with open label topical verapamil for 6 months. The studies were completed after each patient had been treated and evaluated for 9 months after randomization. RESULTS: Fifty-seven patients were randomized. In total, 94.4% of patients treated for 9 months with topical verapamil experienced improvement in curvature with an average percent curvature change of 61.1% compared with 43.6% curvature improvement at 3 months. At 9 months the average percent plaque change was 84.7% compared with 55% at 3 months. Pain resolution at 9 months was 100% compared with 87.5% at 3 months. Patient perception of erection quality also increased at 9 months to 81.8% compared with 72.7% at 3 months. CONCLUSIONS: Topical verapamil gel proved effective in eliminating pain on erection, decreasing the size of plaque, decreasing curvature, and improving erection quality in patients with Peyronie's Disease. Treatment results improved significantly after 9 months' treatment as compared with 3 months' treatment.

Aerosolized nanostructured itraconazole as prophylaxis against invasive pulmonary aspergillosis.

OBJECTIVE: Prophylactic strategies against invasive pulmonary aspergillosis are often limited by drug interactions and toxicities. Targeted airway delivery of antifungals to the lungs may avoid these pitfalls. We evaluated the effectiveness of an aerosolized nanostructured formulation of itraconazole produced by spray freezing into liquid (SFL) as prophylaxis against invasive pulmonary aspergillosis caused by A. fumigatus. METHODS: Immunocompromised Balb/C mice received either itraconazole by oral gavage (Sporanox Oral Liquid [SOL] 30 mg/kg TID) or by aerosolization (SFL 30 mg/kg via 20 min aerosolizations, or control, BID). Dosing began 2 days prior to pulmonary inoculation with A. fumigatus and continued for 7 days post-inoculation. Changes in lung histopathology were also assessed. In the survival arm, mice were monitored over a 5 day period following discontinuation of therapy and survival was assessed by Kaplan-Meier analysis. RESULTS: SFL survival (35%) was greater compared to control (10%; p=0.03) and SOL (0%; p=0.02). Histopathology demonstrated severe invasive disease involving vessels and small airways in control and SOL animals. SFL animals demonstrated colonization with some invasion predominately of large airways. CONCLUSIONS: Prophylactic aerosolization of nanostructured SFL significantly improved survival and limited invasive disease of small airways due to A. fumigatus.