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Henry A PunziTrinity Hypertension and Metabolic Research Institute, Punzi Medical Center, Carrollton, TX, USA; Department of Family and Community Medicine, UT Southwestern Medical Center, Dallas, TX, USAAbstract: Hypertension affects nearly one-third of all individuals in the US, yet one-half of all treated patients achieve blood pressure (BP) controlled to recommended goals. The percentage of patients with uncontrolled BP is likely to be much higher when considering the number of patients who are not even aware of their hypertensive state. Elevated BP is associated with increased risks of cardiovascular events and end-organ damage. Antihypertensive monotherapy is not always sufficient to achieve BP goals, and thus more aggressive treatment regimens need to be considered. Antihypertensive combination therapy, which may improve tolerability, offers the benefit of targeting different mechanisms of action. Numerous outcomes studies support the use of a renin–angiotensin system inhibitor as a first-line choice in antihypertensive therapy. This review discusses the benefits of combination therapy with the angiotensin type II receptor blocker olmesartan medoxomil (OM) paired with the thiazide diuretic hydrochlorothiazide (HCTZ). The pharmacokinetic properties of OM will be reviewed in addition to efficacy studies that support OM + HCTZ combination therapy over other possible antihypertensive combinations. Finally, a rationale for choosing HCTZ over another diuretic, chlorthalidone, will also be discussed based on pharmacokinetic differences, clinical concerns, and trends in use.Keywords: antihypertensives, blood pressure, combination therapy, HCTZ

Obesity is a major risk factor for multiple chronic diseases. Anthropometric and imaging approaches are primarily used to assess adiposity, and there is a dearth of techniques to determine the changes in adipose tissue (AT) at the molecular level. Extracellular vesicles (EVs) have emerged as a novel and less invasive source of biomarkers for various pathologies. Furthermore, the possibility of enriching cell or tissue-specific EVs from the biofluids based on their unique surface markers has led to classifying these vesicles as "liquid biopsies", offering valuable molecular information on hard-to-access tissues. Here, we isolated small EVs from AT (sEV AT ) of lean and diet-induced obese (DIO) mice, identified unique surface proteins on sEV AT by surface shaving followed by mass spectrometry, and developed a signature of five unique proteins. Using this signature, we pulled out sEV AT from the blood of mice and validated the specificity of isolated sEV AT by measuring the expression of adiponectin, 38 adipokines on an array, and several adipose tissue-related miRNAs. Furthermore, we provided evidence of sEV applicability in disease prediction by characterizing sEV AT from the blood of lean and DIO mice. Interestingly, sEV AT-DIO cargo showed a stronger pro-inflammatory effect on THP1 monocytes compared to sEV AT-Lean and a significant increase in obesity-associated miRNA expression. Equally important, sEV AT cargo revealed an obesity-associated aberrant amino acid metabolism that was subsequently validated in the corresponding AT. Lastly, we show a significant increase in inflammation-related molecules in sEV AT isolated from the blood of nondiabetic obese (>30 kg/m 2 ) individuals. Overall, the present study offers a less-invasive approach to characterize AT.

Background and Purpose: The Systolic Blood Pressure Intervention (SPRINT) randomized trial demonstrated that intensive blood pressure management resulted in slower progression of cerebral white matter hyperintensities, compared with standard therapy. We assessed longitudinal changes in brain functional connectivity to determine whether intensive treatment results in less decline in functional connectivity and how changes in brain functional connectivity relate to changes in brain structure., Materials and Methods: Five hundred forty-eight participants completed longitudinal brain MR imaging, including resting-state fMRI, during a median follow-up of 3.84 years. Functional brain networks were identified using independent component analysis, and a mean connectivity score was calculated for each network. Longitudinal changes in mean connectivity score were compared between treatment groups using a 2-sample t test, followed by a voxelwise t test. In the full cohort, adjusted linear regression analysis was performed between changes in the mean connectivity score and changes in structural MR imaging metrics., Results: Four hundred six participants had longitudinal imaging that passed quality control. The auditory-salience-language network demonstrated a significantly larger decline in the mean connectivity score in the standard treatment group relative to the intensive treatment group ( P = .014), with regions of significant difference between treatment groups in the cingulate and right temporal/insular regions. There was no treatment group difference in other networks. Longitudinal changes in mean connectivity score of the default mode network but not the auditory-salience-language network demonstrated a significant correlation with longitudinal changes in white matter hyperintensities ( P = .013)., Conclusions: Intensive treatment was associated with preservation of functional connectivity of the auditory-salience-language network, while mean network connectivity in other networks was not significantly different between intensive and standard therapy. A longitudinal increase in the white matter hyperintensity burden is associated with a decline in mean connectivity of the default mode network., (© 2023 by American Journal of Neuroradiology.)

Importance: Antihypertensive treatments benefit cerebrovascular health and cognitive function in patients with hypertension, but it is uncertain whether an intensive blood pressure target leads to potentially harmful cerebral hypoperfusion., Objective: To investigate the association of intensive systolic blood pressure (SBP) control vs standard control with whole-brain cerebral blood flow (CBF)., Design, Setting, and Participants: This substudy of the Systolic Blood Pressure Intervention Trial (SPRINT) randomized clinical trial compared the efficacy of 2 different blood pressure-lowering strategies with longitudinal brain magnetic resonance imaging (MRI) including arterial spin labeled perfusion imaging to quantify CBF. A total of 1267 adults 50 years or older with hypertension and increased cardiovascular risk but free of diabetes or dementia were screened for the SPRINT substudy from 6 sites in the US. Randomization began in November 2010 with final follow-up MRI in July 2016. Analyses were performed from September 2020 through December 2021., Interventions: Study participants with baseline CBF measures were randomized to an intensive SBP target less than 120 mm Hg or standard SBP target less than 140 mm Hg., Main Outcomes and Measures: The primary outcome was change in whole-brain CBF from baseline. Secondary outcomes were change in gray matter, white matter, and periventricular white matter CBF., Results: Among 547 participants with CBF measured at baseline, the mean (SD) age was 67.5 (8.1) years and 219 (40.0%) were women; 315 completed follow-up MRI at a median (IQR) of 4.0 (3.7-4.1) years after randomization. Mean whole-brain CBF increased from 38.90 to 40.36 (difference, 1.46 [95% CI, 0.08-2.83]) mL/100 g/min in the intensive treatment group, with no mean increase in the standard treatment group (37.96 to 37.12; difference, -0.84 [95% CI, -2.30 to 0.61] mL/100 g/min; between-group difference, 2.30 [95% CI, 0.30-4.30; P = .02]). Gray, white, and periventricular white matter CBF showed similar changes. The association of intensive vs standard treatment with CBF was generally similar across subgroups defined by age, sex, race, chronic kidney disease, SBP, orthostatic hypotension, and frailty, with the exception of an indication of larger mean increases in CBF associated with intensive treatment among participants with a history of cardiovascular disease (interaction P = .05)., Conclusions and Relevance: Intensive vs standard antihypertensive treatment was associated with increased, rather than decreased, cerebral perfusion, most notably in participants with a history of cardiovascular disease., Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.

The dodecapeptide angiotensin-(1-12) [Ang-(1-12)] functions as an intracrine/paracrine substrate for local production of angiotensin II. We developed a reliable and specific radioimmunoassay (RIA) method for the measurement of Ang-(1-12) in human plasma and urine using an affinity purified antibody fraction directed towards the C-terminus of the human Ang-(1-12) sequence. The RIA method was applied to quantify the Ang-(1-12) in plasma and urine collected from thirty-four human subjects (29 treated with antihypertensive medicines and 5 untreated patients). Plasma Ang-(1-12) level was significantly higher (P < 0.05) in patients with systolic blood pressure ≥140 mm Hg (n = 10) compared to the group with systolic blood pressure <140 mm Hg (n = 24). No significant difference (P = 0.22) was found in spot urine between the groups. Our study also shows that the polyclonal antibody neutralizes the cleavage sites of the human Ang-(1-12) from recombinant human chymase (rhChymase) and serum angiotensin converting enzyme (ACE) mediated Ang II generating hydrolysis. Overall, this newly developed RIA method is reliable and applicable to accurately quantify the Ang-(1-12) level in clinical samples (plasma and urine). Further, our in vitro neutralization study suggests that the anti-Ang-(1-12)-antibody might be used as an in vivo therapeutic agent for preventing Ang-(1-12)/Ang II-mediated hypertension and organ damage., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Hyperuricemia is associated with hypertension, with elevated serum uric acid levels postulated to have a causal role in the development of hypertension. Consequently, serum uric acid reduction may help lower blood pressure (BP). A Phase 2, double-blind, placebo-controlled trial was conducted to assess the potential BP-lowering effects of the xanthine oxidase inhibitor febuxostat in subjects with hypertension and hyperuricemia (serum uric acid ≥0.42 mmol/L [≥7.0 mg/dL])., Methods and Results: Subjects (n=121) were randomized 1:1 to febuxostat 80 mg once daily or to placebo. The primary end point was change from baseline to Week 6 in 24-hour mean ambulatory systolic BP (SBP). Additional end points included the following: change from baseline to Week 3 in 24-hour mean SBP and changes from baseline to Weeks 3 and 6 in 24-hour mean ambulatory diastolic BP, serum uric acid, mean daytime and nighttime ambulatory SBP/diastolic BP, and clinic SBP/diastolic BP. For the overall study population, there were no significant differences between febuxostat and placebo for changes from baseline to Weeks 3 or 6 in ambulatory, daytime or nighttime, or clinic SBP or diastolic BP. However, in a preplanned subgroup analysis, there was a significant decrease in SBP from baseline to Week 6 in subjects with normal renal function (estimated glomerular filtration rate ≥90 mL/min) treated with febuxostat versus placebo; least squares mean difference, -6.7; 95% confidence interval -13.3 to -0.0; P =0.049., Conclusions: This study suggests that febuxostat may lower BP in hyperuricemic patients with hypertension and normal renal function; further studies should be conducted to confirm this finding., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01496469., (© 2017 The Authors and Takeda Pharmaceuticals. Published on behalf of the American Heart Association, Inc., by Wiley.)

Objective: To assess the efficacy and safety of once daily olmesartan medoxomil (OM)/amlodipine besylate (AM)/hydrochlorothiazide (HCTZ) 40/10/25 mg in patients with hypertension not at goal with mono, dual or triple drug therapy., Methods: This was a single-center, prospective, open-label, blinded-endpoint study. After a 1-week screening visit, 40 patients were enrolled into the study and given once daily treatment with OM/AM/HCTZ after the patients underwent baseline ambulatory blood pressure monitoring (ABPM) on their original therapy. The primary endpoint was changes from baseline in mean 24 h ABPM [systolic blood pressure (SBP)] after the first day of therapy with OM/AM/HCTZ 40/10/25 mg. Secondary endpoints were changes from baseline in mean 24 h ABPM [diastolic blood pressure (DBP)] after the first day of therapy with OM/AM/HCTZ 40/10/25 mg; mean changes from baseline in trough seated SBP (SeSBP) at day 1 and SeSBP at weeks 1, 2, 3 and 4; mean changes from baseline in trough seated DBP (SeDBP) at day 1 and SeDBP at weeks 1, 2, 3 and 4; and the percentage of subjects achieving mean 24 h, daytime and night-time ABPM BP goals., Results: The baseline paired t-test systolic ABPM was 134.0 ± 2.77 mmHg and day 1 was 128.6 ± 2.47 mmHg with a treatment difference of -5.55 ± 1.3 mmHg (p<0.0001). At week 1, paired t-test ABPM SBP reduction was 117.7 ± 2.0 mmHg with a treatment difference of -16.5 ± 1.8 mmHg (p < 0.0001). At week 2, paired t-test ABPM SBP reduction was 115.8 ± 1.8 mmHg with a treatment difference of -18.4 ± 2.0 mmHg (p < 0.0001). At week 3, paired t-test ABPM SBP reduction was 115.5 ± 1.9 mmHg with a treatment difference of -18.6 ± 2.0 mmHg (p < 0.0001). At week 4, paired t-test ABPM SBP reduction was 115.5 ± 1.8 mmHg with a treatment difference of -18.6 ± 2.2 mmHg (p < 0.0001). The baseline paired t-test SeSBP was 142 ± 2.43 mmHg and day 1 was 132 ± 2.59 mmHg with a treatment difference of -9.78 ± 1.51 mmHg (p < 0.0001). At week 1, paired t-test SeSBP reduction was 124.0 ± 1.6 mmHg with a treatment difference of -17.9 ± 1.8 mmHg (p < 0.0001). At week 2, paired t-test SeSBP reduction was 120.3 ± 1.7 mmHg with a treatment difference of -21.5 ± 2.1 mmHg (p < 0.0001). At week 3, paired t-test SeSBP reduction was 118.5 ± 1.8 mmHg with a treatment difference of -23.3 ± 1.7 mmHg (p < 0.0001). At week 4, paired t-test SeSBP reduction was 119.6 ± 1.7 mmHg with a treatment difference of -22.2 ± 1.9 mmHg (p < 0.0001)., Conclusion: Treatment with OM/AM/HCTZ achieved superior (SBP) ABPM reductions compared with mono, dual or triple drug therapy, resulting in all patients achieving systolic ABPM goal without ABPM documented hypotension.

The subanalysis of a 4 × 4 factorial, 8-week study to evaluate the efficacy and tolerability of telmisartan (T) 40-80 mg/amlodipine (A) 5-10 mg used in treatment-naïve patients (n = 231) and patients previously treated with antihypertensive agents (n = 880). Similar blood pressure (BP) reductions were achieved with T + A, regardless of their pretreatment status. Highest reductions were achieved with T80 + A10 (treatment-naïve -26.5/-18.2 mm Hg and previously treated -25.6/-19.9 mm Hg). Most patients (treatment-naïve 72.4% and previously treated 77.6%), including those with added risk, achieved BP goal (<140/90 mm Hg) with T80 + A10. Tolerability was comparable in both groups.

Introduction: A predefined exploratory analysis of a prospective, randomized, double-blind, forced-titration study of olmesartan medoxomil (OM) versus losartan potassium (LOS) in subjects with hypertension not previously or previously treated with antihypertensive medication is reported., Methods: The study included a 3-4-week placebo run-in and an 8-week active treatment period: OM (weeks 1-4, OM 20 mg; weeks 5-8, OM 40 mg); placebo + OM (weeks 1-2, placebo; weeks 3-4, OM 20 mg; weeks 5-8, OM 40 mg); and LOS (weeks 1-4, LOS 50 mg; weeks 5-8, LOS 100 mg). Analyses focused on comparison of OM and placebo + OM combined versus LOS. Efficacy endpoints were mean change from baseline in seated cuff diastolic blood pressure (SeDBP) at week 8 (primary); seated cuff systolic blood pressure (SeSBP) at weeks 4 and 8, and SeDBP at week 4 (secondary), and BP target achievement (tertiary)., Results: The randomized population (n = 941) had a mean ± SD age of 51.9 ± 9.7 years, 54.5% were male, and 20.1% were naïve to antihypertensive medication. For treatmentnaïve subjects, baseline seated BP (SeBP) (±SD) was 157.4 (±10.9)/101.8 (±4.3) mmHg with OM and 156.3 (±10.8)/101.1 (±3.9) mmHg with LOS, while non-naïve subjects had 158.4 (±10.2)/100.9 (±4.0) mmHg with OM and 158.8 (±10.1)/101.3 (±4.2) mmHg with LOS. OM monotherapy produced significantly greater changes in least-squares mean (±SE) SeDBP compared with LOS in both treatment-naïve (-9.7 [1.0] vs. -6.6 [1.0] mmHg; P = 0.0232 vs. LOS) and non-naïve subjects (-9.6 [0.5] vs. -7.3 [0.5] mmHg; P = 0.0013 vs. LOS). A significantly greater proportion of patients achieved the SeBP goal of <140/90 mmHg with OM compared with LOS in treatment-naïve (34.1% vs. 19.0%, respectively; P = 0.0109) and non-naïve subjects (31.0% vs. 19.6%; P = 0.0008)., Conclusion: Overall, OM monotherapy resulted in significantly greater SeBP reductions and greater SeBP goal achievement than LOS, irrespective of previous medication use. Both OM and LOS therapy were well tolerated.

Objective: To evaluate the comparative efficacy and safety of once-daily olmesartan medoxomil (OM) and losartan potassium (LOS) in patients with hypertension., Methods: This was a multicenter, prospective, randomized, double-blind, active-comparator, forced-titration study. After a 3-week placebo run-in, 941 patients were randomized in an 8:1:9 ratio to once-daily treatment with OM (20 mg for 4 weeks, then OM 40 mg for 4 weeks [n = 420]), placebo plus OM (placebo for 2 weeks, then OM 20 mg for 2 weeks and OM 40 mg for 4 weeks [n = 52]), or LOS (50 mg for 4 weeks, then LOS 100 mg for 4 weeks [n = 469]). A subset of 246 patients underwent ambulatory blood pressure (BP) monitoring. The primary endpoint was mean change from baseline in trough seated cuff diastolic BP (SeDBP) at week 8. Secondary endpoints were mean changes from baseline in trough SeDBP at week 4 and seated systolic BP (SeSBP) at weeks 4 and 8. Tertiary endpoints included change from baseline in mean 24-hour ambulatory BP at weeks 4 and 8 and percentage of patients achieving seated cuff BP (SeBP) goal of < 140/90 mm Hg and mean 24-hour ambulatory BP target of < 130/80 mm Hg at weeks 4 and 8., Results: At week 8, least-squares (LS) mean (± standard error) SeDBP reductions from baseline were 9.7 ± 0.5 and 7.1 ± 0.5 mm Hg (treatment difference: -2.5 ± 0.6 mm Hg; P < 0.0001) and LS mean SeSBP reductions were 13.6 ± 0.7 and 9.7 ± 0.7 mm Hg (treatment difference: -3.9 ± 1.0 mm Hg; P = 0.0001) for OM versus LOS, respectively. A significantly greater proportion of patients receiving OM reached SeBP goal of < 140/90 mm Hg at week 8. There was a similar incidence of adverse events with OM and LOS., Conclusion: Treatment with low- and high-dose OM achieved superior SeBP reductions compared with low- and high-dose LOS, resulting in significantly more patients achieving SeBP goal, with similar tolerability.

In at least 50% of patients with hypertension, particularly those with stage 2 hypertension, combination drug therapy is required to achieve the currently recommended blood pressure (BP) goals. It is likely that future hypertension guidelines will recommend lowering BP beyond the currently recommended systolic/diastolic BP goals of lower than 140/90 mmHg for all patients with hypertension and lower than 130/80 mmHg for patients with diabetes or chronic kidney disease. In a series of clinical trials, the combination of olmesartan medoxomil, a well-established angiotensin receptor blocker, and hydrochlorothiazide, a thiazide diuretic, has produced greater reductions in systolic BP and diastolic BP and greater proportions of patients achieving BP goals than monotherapy with either component. Additionally, the increased efficacy resulting from the combination with hydrochlorothiazide does not appear to significantly affect the tolerability profile of olmesartan medoxomil. This article provides a comprehensive evaluation of the chemistry, clinical efficacy, safety and tolerability of this combination and discusses its role in the management of hypertension.

Background and Objective: A common adverse effect of niacin therapy is flushing, manifested by cutaneous warmth, redness, itching and/or tingling. The Flushing ASsessment Tool (FAST) was developed to assess flushing symptoms and their impact on patients receiving niacin therapy. This study evaluated the reliability, validity and responsiveness of the FAST. The minimal important difference (MID) of the FAST was also examined., Methods: This was a prospective, randomized, double-blind, placebo-controlled, parallel-group 8-week study conducted to evaluate the psychometric characteristics of the FAST. The instrument is administered daily using an electronic patient diary. The study was conducted at 41 clinical sites in the US. 276 patients with dyslipidaemia were randomized to treatment and were at least 18 years of age, with fasting laboratory values of low-density lipoprotein cholesterol (LDL-C) <250 mg/dL and one of the following: high-density lipoprotein cholesterol (HDL-C) <40 mg/dL for males or <50 mg/dL for females; or triglycerides (TG) > or = 150 and < or = 400 mg/dL; or LDL-C > or = 70 mg/dL for patients with a history of coronary heart disease (CHD) or CHD risk equivalents, or > or = 100 mg/dL for subjects with two risk factors, or > or = 160 mg/dL for subjects with 0-1 risk factors. Patients were randomized (1 : 1 : 1) to receive niacin extended-release (NER) 500 mg/day in week 1, 1000 mg/day in week 2 and 2000 mg/day in weeks 3-6/aspirin (acetylsalicylic acid [ASA]), NER/ASA placebo, or NER placebo/ASA placebo., Results: FAST test-retest reliability in stable patients during the first 2 weeks was demonstrated for overall flushing severity using patient and physician overall treatment effect (OTE) ratings (intraclass correlation coefficients of >0.7 for mean overall and individual flushing severity scores). Over the 6-week treatment period, FAST scores demonstrated significant correlations with individual symptoms, impact on daily activities and sleep, and dissatisfaction related to flushing (p < 0.01). Changes in FAST scores were associated with treatment satisfaction (p < 0.01) and patient- and physician-rated OTE (p < 0.01). Using patient-rated OTE, the mean maximum flushing severity scores improved 1.85 points in responders and only 0.18 points in non-responders (p < 0.001); responders were defined by improved patient- or physician-rated OTE. Among patients with flushing, mean maximum overall flushing scores differed between patients who subsequently discontinued due to flushing (7.9 points) and those who did not discontinue (4.7 points; p < 0.001). The probable range in this study for a detectable change in flushing symptoms (MID) was 0.29-0.38 points for mean flushing severity and 0.66-0.86 points for maximum flushing severity., Conclusion: The FAST exhibited test-retest reliability, good evidence of construct validity, and, overall, flushing severity was responsive to change over time. The FAST is a reliable and valid instrument for assessing the impact of niacin-induced flushing in patients with dyslipidaemia.

Background: Most patients with stage 2 hypertension require two or more antihypertensive agents in order to achieve the BP goals recommended in current treatment guidelines. Accordingly, combinations of two drugs with different mechanisms of antihypertensive action are widely used., Objective: The aim of this randomized, double-blind, multicenter 12-week study was to compare the efficacy, safety, and tolerability of a combination of olmesartan medoxomil/hydrochlorothiazide (HCTZ) with that of benazepril plus amlodipine besylate in patients with stage 2 hypertension., Methods: Patients were eligible for randomization following a 3- to 4-week placebo run-in period if they had either (i) mean seated DBP>or=90 mm Hg but<115 mm Hg and mean seated SBP>or=160 mm Hg but <200 mm Hg, or (ii) mean seated DBP>or=100 mm Hg but<115 mm Hg. The difference in mean seated SBP measured on two separate visits during the run-in period was required to beor=95 mm Hg and<115 mm Hg or SBP>145 mm Hg and

To attain recent goals of blood pressure (BP) control, multiple drug therapy combinations are required, including higher doses of thiazide diuretics in combination with other classes of antihypertensive drug therapy. Thus, the authors evaluated the antihypertensive effects of telmisartan vs valsartan when combined with hydrochlorothiazide (HCTZ) 25 mg in a large (N=1066), placebo-controlled trial in patients with stage 1 or 2 hypertension. The primary end points were the changes from baseline in seated diastolic and systolic BP at the end of the 8-week treatment period. Safety end points included adverse events, changes in laboratory parameters, and pulse rate. Changes from baseline in BP following telmisartan-HCTZ (-24.0/-17.6 mm Hg) were significantly greater than both placebo (-4.4/-6.8 mm Hg) and valsartan-HCTZ (-21.2/-16.1 mm Hg) (vs placebo, P<.001 for systolic and diastolic BP; vs valsartan-HCTZ, P=.004 for systolic BP and P=.019 for diastolic BP). The total number of patients with at least 1 adverse event reported were similar among the 3 treatment groups (placebo, 49%; telmisartan-HCTZ, 43%; and valsartan-HCTZ, 38%). In conclusion, telmisartan-HCTZ at doses of 80/25 mg lowered both systolic and diastolic BP to a greater extent than valsartan-HCTZ at doses of 160/25 mg. These data support using a higher dose of a thiazide diuretic (25 mg) with a long-acting angiotensin receptor blocker as a useful strategy for improving hypertension control.

This was a double-blind, randomized, placebo-controlled multicenter, titration-to-effect study of eprosartan in patients > or =60 years of age with isolated systolic hypertension. The study consisted of a 3 to 5-week placebo run-in period, a 13-week double-blind treatment period (6-week titration with eprosartan 600-1200 mg/day, 3-week maintenance, 4-week combination therapy with hydrochlorothiazide/HCTZ 12.5 mg), and a follow-up period within 5-7 days of last treatment dose. Overall, 283 patients (placebo/P: 135; eprosartan /E: 148) were randomized [female patients-P: 55.6%, E:54.7%; white-P:66.7%, E:67.6%). Mean sitting systolic blood pressure (SitSBP) at baseline was comparable (P: 170+/-0.8 mmHg; E: 171+/-0.8 mm Hg). At monotherapy end point, eprosartan produced a significant reduction in SitSBP (E: 16.1 mmHg vs P: 8.4 mmHg; P<0.0001). In all, 57.4% of patients responded to eprosartan monotherapy. Among nonresponders, the addition of HCTZ resulted in a decrease in SitSBP from baseline (E: 21.7 mmHg; P: 14.4 mmHg; P<0.002). Reductions were also noted in Standing SBP (monotherapy: P<0.001; combination therapy: P=0.03). No reductions in SitDBP >4 mmHg were found during the study. Age, gender, and race did not have any impact on the results. Post hoc analysis showed a reduction in pulse pressure from 87.3 to 78.2 mmHg with placebo and from 87.6 to 70.7 mmHg with eprosartan monotherapy. Treatment with eprosartan in once-daily doses up to 1200 mg alone or in combination with HCTZ was well tolerated, with dizziness and asthenia being the most common side effects.

Based on the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT) Trial, the Seventh Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC-7) states that "thiazide-type diuretics should be used as initial therapy for most patients with hypertension." In the ALLHAT study, although there was no difference in the primary outcome for fatal heart attack and nonfatal myocardial infarction between all treatment groups, the manuscript endorses thiazide-type diuretics as first choice, based on their cardioprotective effects and low cost. It is well known that thiazide-type diuretics cause hypokalemia, glucose intolerance, and diabetes, although the ALLHAT study showed a significant 43% to 65% higher risk of new-onset diabetes with chlorthalidone compared with amlodipine (30%) and lisinopril (18%). The investigators justified the fact that the greater incidence of diabetes did not translate into more cardiovascular events. Such a conclusion ignores that the morbidity and mortality from diabetes manifests over decades and not the mere 2- to 6-year time frame examined in the ALLHAT study. It would appear that the strong endorsement of thiazide-type diuretics as first-line therapy by the JNC-7 will lead to a higher incidence of diabetes in these patients.

Factors that affect the reliability and accuracy of blood pressure measurements are reviewed, and new technologies for measuring blood pressure are discussed. Blood pressure measurements obtained in an office, hospital, or clinic are subject to variation and error. Reasons for variations include the wrong cuff size, improper inflation or deflation technique, and patient apprehension ("white-coat syndrome"). Ambulatory blood pressure monitoring (ABPM) involves the use of a fully automated standard arm cuff that is inflated at predetermined intervals by a small battery-powered pump unit. The most reliable ABPM method is the oscillometric method, which detects subtle changes in air pressure within the cuff system caused by fluctuations of the brachial artery. The process for interpreting 24-hour ABPM data is still evolving. Twenty-four-hour ABPM has been shown to eliminate white-coat hypertension and is also useful for assessing patients whose blood pressure is inappropriately high in the absence of end organ damage, monitoring persons at risk of developing hypertension because of their race or family history, determining a medication's 24-hour effect on blood pressure, and assessing the early-morning rapid rise in blood pressure, which has been linked to an increased risk of nonembolic stroke and myocardial infarction. ABPM enables identification of patients whose blood pressure is elevated in the office but normal at home, allows more appropriate screening of patients for clinical trials, gives reproducible values, and enables evaluation of drug duration and action.

BACKGROUND: Twenty-four-hour ambulatory blood pressure monitoring (ABPM), which provides important information regarding mean 24 h efficacy, variability of effect during sleeping-awake cycles, and effects on the early morning surge in blood pressure, is a sensitive method for evaluating efficacy of antihypertensive agents. Extended-release nisoldipine and amlodipine are long-acting dihydropyridine calcium antagonists used for the treatment of hypertension. Because these agents have different pharmacokinetic profiles, 24 h ABPM could provide clues regarding their different effects on blood pressure. OBJECTIVE: To assess the effects of extended-release nisoldipine and amlodipine on 24 h ambulatory blood pressure control and heart rate. METHODS: After completion of a 3-4 week placebo run-in period, 100 patients were randomly allocated to double-blind treatment with 10-40 mg extended-release nisoldipine or 2.5-10 mg amlodipine for 8 weeks, starting at the lowest dose. Medications were titrated at 2-week intervals on the basis of office blood pressures in seated patients. Twenty-four-hour ABPM was performed at placebo baseline and at the end of double-blind therapy. RESULTS: Extended-release nisoldipine and amlodipine provided equivalent mean 24 h changes in blood pressure [systolic blood pressure (SBP)/diastolic blood pressure decreases by 9.8/7.1 and 8.0/6.0 mmHg, respectively] and heart rate. These two treatments also provided similar changes in blood pressure at trough (22-24 h after dosing; decreases by 10.4/7.2 and 10.1/7.3 mmHg, respectively). The antihypertensive effects of amlodipine during the awake and sleeping intervals were similar (decreases by 9.6/5.9 and 9.9/5.8 mmHg, respectively, NS); whereas the effect of nisoldipine during the awake interval was significantly greater than its effect during the sleeping interval (decreases by 12.4/8.0 and 8.9/4.3 mmHg, respectively, P = 0.08/0.01). Furthermore, extended-release nisoldipine, but not amlodipine, blunted the rate of rise in early morning SBP. CONCLUSIONS: Extended-release nisoldipine and amlodipine have similar effects on mean 24 h and trough blood pressures. However, different effects during the sleeping and awake intervals and on the rate of rise in early morning SBP were observed with nisoldipine.

Overall, angiotensin-converting enzyme (ACE) inhibitors have a very low side-effect profile. However, several reports in the literature cite cough as a possible complication of ACE inhibitor therapy. These reports have prompted speculation that the risk of cough may differ among ACE inhibitors and that the risk may be greater in patients with renal impairment, perhaps because of excessive drug accumulation. However, these hypotheses have not been tested in prospective, controlled studies. Fosinopril is a long-acting ACE inhibitor with a unique chemical structure and an elimination profile that is associated with stable clearance, regardless of the degree of renal impairment. Favorable clinical experience with fosinopril led to the evaluation of this agent's cough profile in a prospective, open-label study. This study focused on the frequency of cough in patients with mild-to-moderate hypertension who had previously experienced cough while taking another ACE inhibitor. Whereas most prior controlled studies and postmarketing surveillance trials measured the frequency of cough through spontaneous adverse-event reporting, in this study a methodology previously validated in antitussive and mucolytic studies was adapted to provide accurate and sensitive measure of fosinopril's cough profile. Twenty-four patients were switched from another ACE inhibitor to fosinopril, 10 mg once daily for 6 weeks. At study end, the mean occurrence of cough, frequency of cough, and cough severity significantly changed from baseline (p < or = 0.0002). Thus, fosinopril use was associated with a less frequent, less severe cough in patients who experienced cough while taking other ACE inhibitors.

A multicentre, randomised, placebo-controlled parallel group study comparing various doses of the combination diltiazem SR (DTZ SR)/hydrochlorothiazide (HCTZ) with the monotherapies was performed to delineate the optimal antihypertensive dosage of the two drug combinations. The study was carried out in 298 patients with mild to moderate essential hypertension (stable supine diastolic blood pressure, DBP, greater than or equal to 95 and less than or equal to 110 mmHg). After a single-blind placebo lead-in period lasting 4-6 weeks to establish stable baseline BP, the patients were randomised to receive either placebo (n = 75), HCTZ (n = 76), DTZ SR (n = 72), or the combination of DTZ SR/HCTZ (n = 75). There were three 4-week evaluation periods with forced escalation of therapy as follows: HCTZ (6.25, 6.25, 12.5 mg twice daily), DTZ SR (60, 90, 120 mg twice daily), and the combination of DTZ SR/HCTZ (60/6.25, 90/6.25, 120/12.5 mg twice daily). DTZ SR/HCTZ (120/12.5 mg) produced statistically significantly greater reductions in supine DBP compared with each monotherapy and placebo. The lower doses of DTZ SR/HCTZ (60/6.25 mg and 90/6.25 mg) produced statistically significantly greater supine DBP reductions compared with DTZ SR monotherapy and placebo, but not compared with HCTZ monotherapy. A comparison of reduction in supine DBP between evaluation periods demonstrated a dose-response relationship for the combination therapy in reducing BP over the dosage range studied. Adverse clinical and laboratory events were not significantly different between the therapies.(ABSTRACT TRUNCATED AT 250 WORDS)

The dipping of snuff provoked paroxysmal hypertension that induced myocardial ischemia in a 69-year-old woman with pheochromocytoma. The diagnosis of her tumor was delayed by a report of a falsely low urine metanephrine level, resulting from interference with the metanephrine assay by meglumine present in the urine because of contrast coronary angiography performed on the day of urine collection.