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Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10-8) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.© 2014 Nature America, Inc. All rights reserved.

Background- LCI699, a novel inhibitor of aldosterone synthase, reduces serum aldosterone, and may have benefit in the treatment of hypertension. Methods and Results- We performed the first double-blind, randomized trial with LCI699 in patients with primary hypertension. We randomized 524 patients to LCI699 0.25 mg once daily (n=92), 0.5 mg once daily (n=88), 1.0 mg once daily (n=86), and 0.5 mg twice daily (n=97); eplerenone 50 mg twice daily (n=84); or placebo (n=77) for 8 weeks. Adrenocorticotropic hormone (250 [mu]g IV) stimulation testing was performed in a subset of patients to quantify the selectivity of LCI699 for aldosterone synthase compared with 11-[beta]-hydroxylase. Reductions in clinic diastolic blood pressure were significant for LCI699 1.0 mg (-7.1 mm Hg; P=0.0012) and eplerenone 50 mg twice daily (-7.9 mm Hg; P<0.0001) compared with placebo (-2.6 mm Hg) but not other doses of LCI699. Significant reductions in clinic systolic blood pressure were observed with all doses of LCI699 (P<0.005 or better) and eplerenone (P<0.0001). All doses of LCI699 significantly reduced 24-hour ambulatory blood pressure compared with placebo (P<0.01). Adrenocorticotropic hormone stimulation of cortisol was suppressed in ~=20% of subjects receiving LCI699 at a total daily dose of 1.0 mg. Safety and tolerability were similar among LCI699, placebo, and eplerenone. Conclusions- Aldosterone synthase inhibition with LCI699 significantly lowered clinic and ambulatory blood pressure. A minority of subjects developed blunted adrenocorticotropic hormone-stimulated release of cortisol. These results support additional research to evaluate use of aldosterone synthase inhibition in primary hypertension and/or patients characterized by aldosterone excess. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00758524. [ABSTRACT FROM AUTHOR]

Context: Patients with chronic disabling gout refractory to conventional urate-lowering therapy need timely treatment to control disease manifestations related to tissue urate crystal deposition. Pegloticase, monomethoxypoly(ethylene glycol)-conjugated mammalian recombinant uricase, was developed to fulfill this need.Objective: To assess the efficacy and tolerability of pegloticase in managing refractory chronic gout.Design, Setting, and Patients: Two replicate, randomized, double-blind, placebo-controlled trials (C0405 and C0406) were conducted between June 2006 and October 2007 at 56 rheumatology practices in the United States, Canada, and Mexico in patients with severe gout, allopurinol intolerance or refractoriness, and serum uric acid concentration of 8.0 mg/dL or greater. A total of 225 patients participated: 109 in trial C0405 and 116 in trial C0406.Intervention: Twelve biweekly intravenous infusions containing either pegloticase 8 mg at each infusion (biweekly treatment group), pegloticase alternating with placebo at successive infusions (monthly treatment group), or placebo (placebo group).Main Outcome Measure: Primary end point was plasma uric acid levels of less than 6.0 mg/dL in months 3 and 6.Results: In trial C0405 the primary end point was reached in 20 of 43 patients in the biweekly group (47%; 95% CI, 31%-62%), 8 of 41 patients in the monthly group (20%; 95% CI, 9%-35%), and in 0 patients treated with placebo (0/20; 95% CI, 0%-17%; P < .001 and <.04 for comparisons between biweekly and monthly groups vs placebo, respectively). Among patients treated with pegloticase in trial C0406, 16 of 42 in the biweekly group (38%; 95% CI, 24%-54%) and 21 of 43 in the monthly group (49%; 95% CI, 33%-65%) achieved the primary end point; no placebo-treated patients reached the primary end point (0/23; 95% CI, 0%-15%; P = .001 and < .001, respectively). When data in the 2 trials were pooled, the primary end point was achieved in 36 of 85 patients in the biweekly group (42%; 95% CI, 32%-54%), 29 of 84 patients in the monthly group (35%; 95% CI, 24%-46%), and 0 of 43 patients in the placebo group (0%; 95% CI, 0%-8%; P < .001 for each comparison). Seven deaths (4 in patients receiving pegloticase and 3 in the placebo group) occurred between randomization and closure of the study database (February 15, 2008).Conclusion: Among patients with chronic gout, elevated serum uric acid level, and allopurinol intolerance or refractoriness, the use of pegloticase 8 mg either every 2 weeks or every 4 weeks for 6 months resulted in lower uric acid levels compared with placebo.Trial Registration: clinicaltrials.gov Identifier: NCT00325195. [ABSTRACT FROM AUTHOR]

In April 2008, a panel was convened to discuss the effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in the treatment of hypertension and the possible added benefit of using these agents together. The panel was moderated by Marvin Moser, MD, Clinical Professor of Medicine at Yale University School of Medicine, and included Clive Rosendorff, MD, PhD, Professor of Medicine at Mount Sinai School of Medicine and William B. White, MD, Division Chief, Hypertension and Clinical Pharmacology and Professor, Calhoun Cardiology Center at the University of Connecticut Health Center, Farmington. [ABSTRACT FROM AUTHOR]

To determine whether the cyclooxygenase-2 (COX-2) inhibitor celecoxib affects cardiovascular thrombotic risk, we analyzed the incidence of cardiovascular events for celecoxib, placebo, and nonsteroidal anti-inflammatory drugs (NSAIDs) in the entire controlled, arthritis clinical trial database for celecoxib. The primary analysis used the Antiplatelet Trialists' Collaboration end points, which include: (1) cardiovascular, hemorrhagic, and unknown deaths, (2) nonfatal myocardial infarction, and (3) nonfatal stroke. Other secondary thrombotic events were also examined. Separate analyses were performed for all patients and for those not taking aspirin. Data from all controlled, completed arthritis trials of > or =4 weeks duration, including 13 new drug application studies and 2 large post-marketing trials (CLASS and SUCCESS) were included for analyses. Patients were randomized to celecoxib at doses from 100 to 400 mg twice daily (18,942 patients; 5,668.2 patient-years of exposure), diclofenac 50 to 75 mg twice daily, ibuprofen 800 mg thrice daily, naproxen 500 mg twice daily (combined NSAID exposure of 11,143 patients; 3,612.2 patient-years), or placebo (1,794 subjects; 199.9 subject-years). Data from a long-term uncontrolled trial with 5,209 patients (6,950 patients-years) treated with celecoxib were included in a supplemental analysis. The entire 15-trial database was searched for possible serious thrombotic events as well as to identify all deaths. For these patients, detailed clinical data were obtained and reviewed by 2 of the investigators (WBW and JSB), who were independently and blinded to exposure, to classify the event as primary, secondary, or neither. All analyses were done using the intent-to-treat population, and time-to-event analyses were performed using per-patient data. To examine heterogeneity of results among studies, tests of interaction were performed using the Cox model. Incidences of the primary and secondary events were not significantly different between the celecoxib and placebo groups, nor for the celecoxib group compared with the NSAIDs group, regardless of aspirin use and NSAID type. The relative risks comparing celecoxib with the NSAIDs for the primary events were 1.06 (95% confidence interval 0.70 to 1.61, p = 0.79) for all patients, and 0.86 (95% confidence interval 0.48 to 1.56, p = 0.62) for the subgroup not taking aspirin. Similarly, for secondary cardiovascular end points, all relative risks were < or =1 for celecoxib compared with either placebo or NSAIDs. These comparative analyses demonstrate no evidence of increased risk of cardiovascular thrombotic events associated with celecoxib compared with either conventional NSAIDs or placebo. [ABSTRACT FROM AUTHOR]

Eplerenone is a highly selective aldosterone blocking agent, which was recently approved for the treatment of hypertension and has also been shown to reduce mortality in post-myocardial infarction patients with heart failure. To assess its usefulness in patients with essential hypertension, we performed a 12-week, double-blind, placebo-controlled, parallel-arm, fixed-dose study over a range of doses using clinic and ambulatory blood pressure (BP). After single-blind placebo therapy for 3 to 4 weeks to obtain baseline measures, 400 patients were randomized to receive placebo or 1 of 4 doses of eplerenone (25, 50, 100, and 200 mg once daily). In addition, changes from baseline in serum potassium, active renin activity, and serum aldosterone were assessed. After 12 weeks of therapy, reductions in clinic BP showed a significant dose response in which 25 mg of eplerenone achieved statistical significance compared with placebo for systolic BP; maximum clinic BP reduction was achieved with the 100 mg dose. Ambulatory BP monitoring showed that all doses of eplerenone (25 to 200 mg/day) lowered BP significantly greater than placebo with a significant dose response. The 24-hour mean BP reductions ranged from 6.4/4.4 to 10.3/5.7 mm Hg on eplerenone compared with 1.3/0.8 mm Hg on placebo. One patient on placebo and 1 patient on 200 mg of eplerenone had episodes of elevated serum potassium levels (>5.5 mEq/L). Increases in serum aldosterone were related to dose but not to reductions in 24-hour BP. Side effects and withdrawal rates attributed to eplerenone were similar to those of placebo. These data show that eplerenone is an effective antihypertensive agent at doses as low as 25 mg/day. The top effective dose in stage 1 to 3 hypertension based on clinic and ambulatory BP was 100 mg once daily. The incidence of elevated serum potassium levels was not increased across doses of eplerenone in this study. [ABSTRACT FROM AUTHOR]

Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs), including the cyclooxygenase-2 (COX-2) specific inhibitors, with antihypertensive medication is common practice for many patients with arthritis. This study evaluated the effects of celecoxib 200 mg/day and rofecoxib 25 mg/day on blood pressure (BP) and edema in a 6-week, randomized, parallel-group, double-blind study in patients > or =65 years of age with osteoarthritis who were treated with fixed antihypertensive regimens. One thousand ninety-two patients received study medication (celecoxib, n = 549; rofecoxib, n = 543). Significantly more patients in the rofecoxib group compared with the celecoxib group developed increased systolic BP (change >20 mm Hg plus absolute value > or =140 mm Hg) at any time point (14.9% vs 6.9%, p <0.01). Rofecoxib caused the greatest increase in systolic BP in patients receiving angiotensin-converting enzyme inhibitors or beta blockers, whereas those on calcium channel antagonists or diuretic monotherapy receiving either celecoxib or rofecoxib showed no significant increases in BP. Clinically significant new-onset or worsening edema associated with weight gain developed in a greater percentage of patients in the rofecoxib group (7.7%) compared with the celecoxib group (4.7%) (p <0.05). Thus, in patients with controlled hypertension on a fixed antihypertensive regimen, careful monitoring of BP is warranted after the initiation of celecoxib or rofecoxib therapy. [ABSTRACT FROM AUTHOR]

It has been hypothesized that cyclooxygenase 2 specific inhibitors may increase the risk of cardiovascular (CV) thromboembolic events because of their inhibition of vascular prostacyclin synthesis and lack of an effect on platelet thromboxane A(2) production and aggregation. Thus, we analyzed the data for celecoxib and nonsteroidal anti-inflammatory drugs (NSAIDs) from the Celecoxib Long-term Arthritis Safety Study to determine the incidences of serious CV thromboembolic events. This trial included 3,987 persons randomized to celecoxib 400 mg twice daily (2,320 person-years of exposure) and 3,981 persons randomized to either ibuprofen 800 mg 3 times daily or diclofenac 75 mg twice daily (2,203 person-years). Because acetylsalicylic acid (ASA) use for CV risk prophylaxis (< or =325 mg/day) was permitted, separate analyses were performed for all patients and those not taking ASA. The incidences of serious CV thromboembolic events (myocardial infarction, stroke, CV deaths, and peripheral events) were similar, and not significantly different, between celecoxib and NSAID comparators (combined or individually) for all patients as well as the subgroup of patients not taking ASA. This observation was true both for all serious CV thromboembolic events, as well as for individual events. No increase in myocardial infarction was apparent, even in patients not taking ASA who were candidates for secondary prophylaxis for myocardial infarction. The relative risks for celecoxib versus NSAIDs for serious CV thromboembolic events were 1.1 for all patients and 1.1 for the subgroup of patients not taking ASA (95% confidence interval 0.7 to 1.6 and 0.6 to 1.9, respectively). In addition, the incidences of adverse CV events such as hypertension, edema, and congestive heart failure were similar to, or significantly lower than, NSAID comparators regardless of the use of ASA. Thus, these analyses demonstrate no increased risk of serious CV thromboembolic events associated with celecoxib compared with conventional NSAIDs and therefore do not support the hypothesis of a class adverse effect of cyclooxygenase 2 specific inhibitors on the CV system. [ABSTRACT FROM AUTHOR]

The objectives of this double-blind, multicenter, randomized, parallel-arm, placebo-controlled study were to evaluate the dose-related efficacy, tolerability, and safety of candesartan cilexetil, a potent, AT1 selective, long-acting angiotensin II receptor blocker, in 365 adult patients with systemic hypertension and mean sitting diastolic blood pressure (BP) of 95 to 114 mm Hg. Patients received either placebo or candesartan cilexetil 2, 4, 8, 16, or 32 mg once daily for 8 weeks. All doses of candesartan cilexetil reduced trough (24 hours after treatment) sitting diastolic and systolic BP significantly compared with placebo (p < 0.005). A significant (p < or = 0.0001) dose response was evident, with greater decreases in BP at higher doses. Mean changes in BP were -10.7/-7.8 mm Hg and -12.6/-10.2 mm Hg in the 16- and 32-mg groups, respectively, versus -0.3/-2.6 mm Hg in the placebo group. The 16- and 32-mg doses were consistently significantly superior to placebo in antihypertensive effect with regard to all BP measurements, including peak (6 hours after treatment), trough, sitting, and standing measurements of diastolic and systolic BP. Responder rates (trough sitting diastolic BP < 90 or > or = 10 mm Hg BP decrease) were 54% and 64% for the 16- and 32-mg groups, respectively. Tolerability and safety profiles were similar to placebo at all doses. In conclusion, candesartan cilexetil administered once daily effectively reduces BP in a dose-related manner while maintaining safety and tolerability; doses of 16 and 32 mg are most effective for treatment of hypertension. [ABSTRACT FROM AUTHOR]

We assessed the differential effects of a chronotherapeutic agent (controlled-onset extended release [COER] verapamil), administered at bedtime versus a conventional, homeostatic therapy (nifedipine gastrointestinal therapeutic system [GITS]) taken in the morning, on early morning and 24-hour blood pressure (BP), heart rate (HR), and the HR x systolic BP product. The study was a multicenter (n = 51), randomized, double-blind prospective clinical trial with a 10-week treatment period. Dose titration was performed by study investigators based on systolic and diastolic BP values at the doctor's office. Ambulatory BP monitoring was performed at placebo baseline, after 4 weeks of stable double-blind therapy, and at end of the study. Twenty-four-hour BP profiles were studied in 557 hypertensive patients. Changes in BP, HR, slope of the rate of rise of BP and HR, and the HR-systolic BP product during the 4 hours from 1 hour before to 3 hours after awakening were evaluated. The study was powered to show equivalence between the 2 regimens, predefined as a difference between treatment groups in mean change from baseline in early morning BP of +/- 5 mm Hg systolic and +/- 3 mm Hg diastolic. Changes in the early morning BP fell within the definition of equivalence for the 2 treatment strategies (-12.0/-8.2 mm Hg for COER-verapamil and -13.9/-7.3 mm Hg for nifedipine GITS). Changes in both the early morning HR and rate-pressure product were significantly greater following COER-verapamil therapy versus nifedipine GITS (HR, -3.8 beats/minute vs +2.6 beats/minute, p < 0.001 and HR-systolic BP product, -1,437 beats/min x mm Hg vs -703 beats/min x mm Hg, respectively, p < 0.001). Changes in ambulatory BP demonstrated clinically similar reductions for the awake period, but nifedipine GITS lowered systolic BP to a greater extent than COER-verapamil during sleep (-11.0 vs -5.8 mm Hg, p < 0.001). COER-verapamil and nifedipine GITS had equivalent effects (+/- 5/3 mm Hg) on early morning BP. In addition, both extended-release calcium antagonists effectively lowered 24-hour BP. However, COER-verapamil had greater effects than nifedipine GITS on early morning hemodynamics (HR, HR-systolic BP product, rate of rise of BP and HR) and lesser effects during sleep due to its intrinsic pharmacologic properties and chronotherapeutic delivery system. [ABSTRACT FROM AUTHOR]

An abstract of the article "Utility of semi-automated clinic and 24 hour ambulatory blood pressure measurements to evaluate fixed-dose combination therapy: The ramipril-hydrochloritiazide hypertension trial," by W.B White and colleagues is presented.

In this article, 2 leading physicians debate the strength of outcome data on the efficacy of angiotensin-converting enzyme (ACE) inhibitors versus angiotensin II receptor blockers (ARBs) for reducing the incidence of cardiovascular, cerebrovascular, and renovascular events. Dr. Stephen G. Ball notes that the efficacy of ACE inhibitors for reducing the risk for myocardial infarction independent of their effects on blood pressure is controversial. In the Heart Outcomes Prevention Evaluation (HOPE) study, ramipril treatment in high-risk patients was associated with a 20% reduction in the risk for myocardial infarction; mean reduction in blood pressure was 3 mm Hg for systolic blood pressure and 1 mm Hg for diastolic blood pressure. The HOPE investigators propose that the 20% reduction was much greater than would be expected based on the observed blood pressure reduction. However, a meta-regression analysis of blood pressure reduction in >20 antihypertensive therapy outcome trials found that the reduction in myocardial infarction risk with ramipril observed in HOPE was consistent with the modest blood pressure reduction seen with that agent. Nevertheless, there are convincing data for prevention of myocardial infarction with ACE inhibitors in patients with heart failure, including those with heart failure after myocardial infarction, as well as supportive evidence from studies in patients with diabetes mellitus and concomitant hypertension. On the other hand, Dr. William B. White takes the position that ARBs are well-tolerated antihypertensive agents that specifically antagonize the angiotensin II type 1 (AT(1)) receptor and provide a more complete block of the pathologic effects of angiotensin II-which are mediated via the AT(1) receptor-than ACE inhibitors. The Evaluation of Losartan in the Elderly (ELITE) II study and the Valsartan Heart Failure Trial (ValHeFT) suggest that ARBs reduce the risk for mortality in patients with congestive heart failure. The Losartan Intervention for Endpoint (LIFE) Reduction in Hypertension trial also demonstrated beneficial effects of ARBs in the prevention of stroke events. The Irbesartan in Patients with Diabetes and Microalbuminuria (IRMA) study, the Irbesartan Diabetic Nephropathy Trial (IDNT), and the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study demonstrated significant reductions in the rate of progression of renal disease in patients receiving ARBs, independent of effects on blood pressure. These data support the use of ARBs, in addition to the standard of care, in hypertensive patients with heart failure who are intolerant of ACE inhibitors, and also provide compelling evidence for their use in patients with hypertension and type 2 diabetes. [ABSTRACT FROM AUTHOR]