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Background Worsening renal function (WRF) portends a poor prognosis, and recent deterioration in creatinine might identify patients with elevated intrarenal adenosine in whom adenosine A 1 antagonism may improve renal hemodynamics and function. The purpose of this pilot study was to assess whether rolofylline, an adenosine A 1 antagonist (A 1 RA), would facilitate diuresis while maintaining renal function in patients with acutely decompensated heart failure (ADHF) and recent WRF. Methods and Results Seventy-six patients with ADHF, volume overload, and recent renal deterioration received rolofylline (30 mg, n = 36) or placebo (n = 40) for 3 days. Rolofylline did not demonstrate a beneficial effect on the primary end points of worsening heart failure or renal function after admission or death or readmission within 30 days. Similar proportions of patients receiving rolofylline (33%) and placebo (30%) were treatment failures within 30 days. However, persistent renal impairment (through Day 14) tended to be less common with rolofylline (6%) than placebo (18%). At Day 14, 11 patients receiving placebo and 13 patients receiving rolofylline had a decrease in creatinine ≥0.3 mg/dL. There were fewer heart failure readmissions with rolofylline (n = 2) than with placebo (n = 7) through Day 60. Conclusions The Placebo-Controlled Study of the Effects of KW-3902 Injectable Emulsion on Heart Failure Signs and Symptoms, Diuresis, Renal Function, and Clinical Outcomes in Subjects Hospitalized with Worsening Renal Function and Heart Failure Requiring Intravenous Therapy (ie, REACH UP) study did not demonstrate any clear benefit of rolofylline in patients with ADHF and worsening renal function. However, beneficial trends raise the possibility that A 1 RAs might prevent renal dysfunction in these high risk patients. To test this hypothesis, further larger studies need to evaluate the effects of adenosine A 1 antagonists in patients with progressive renal dysfunction in the face of active heart failure therapy.

The percentage of change from baseline in low-density lipoprotein (LDL) cholesterol after the addition of ezetimibe 10 mg to atorvastatin 40 mg was compared with uptitration to atorvastatin 80 mg. In this multicenter, double-blind, parallel-group study, adult hypercholesterolemic patients using atorvastatin 40 mg/day were randomly assigned to atorvastatin 40 mg plus ezetimibe 10 mg or uptitration to atorvastatin 80 mg. After 6 weeks of treatment, compared with atorvastatin 80 mg, atorvastatin 40 mg plus ezetimibe significantly reduced the primary end point of LDL cholesterol by -27% versus atorvastatin 80 mg by -11% (p

The aim of this study was to evaluate the efficacy and safety of ezetimibe 10 mg added to atorvastatin 20 mg compared with doubling atorvastatin to 40 mg in patients with hypercholesterolemia at moderately high risk for coronary heart disease who did not reach low-density lipoprotein (LDL) cholesterol levels

Background Montelukast has proven efficacy in the treatment of chronic asthma and seasonal allergic rhinitis, but it has not been evaluated in the subpopulation of asthmatic patients with seasonal asthma symptoms. Objective To determine the effectiveness of montelukast treatment in improving the control of asthma symptoms during the allergy season in patients with active asthma and seasonal aeroallergen sensitivity. Methods Adults with a history of chronic asthma who are also symptomatic during the allergy season and with skin test sensitivity to seasonal aeroallergens were enrolled in a randomized, parallel-group, multicenter study with a 1-week, single-blind, placebo run-in period followed by 3 weeks of doubleblind treatment during the spring of 2004. After the run-in period, eligible patients were randomly assigned to receive either oral montelukast (10 mg) or placebo. Daytime and nighttime asthma symptom scores, β-agonist use, and morning and evening peak expiratory flow rates were recorded daily using an electronic diary. The primary end point was mean change from baseline to week 3 in the daytime asthma symptom score. Results Of 455 randomized patients, 433 completed the study. Compared with placebo, treatment with montelukast resulted in a significant improvement from baseline in the daytime asthma symptom score (−0.54 vs −0.34; P = .002) and in β-agonist use, nighttime symptoms, and peak expiratory flow rates. Few patients in the montelukast and placebo groups discontinued study participation because of asthma (1.3% and 3.0%, respectively). Conclusion In patients with chronic asthma and seasonal aeroallergen sensitivity, montelukast treatment provided significant asthma control during the allergy season compared with placebo.

To determine analgesic efficacy of a single oral dose of rofecoxib 50 mg compared with acetaminophen/codeine 600/60 mg, we conducted a double-blind, randomized, placebo- and active-comparator-controlled, parallel-group study.Patients (N = 390) experiencing moderate or severe pain postextraction of 2 or more third molars, with at least 1 mandibular impaction, were randomized to placebo (n = 30), rofecoxib (n = 180), or codeine/acetaminophen 60/600 mg (n = 180). Time to confirmed perceptible pain relief, and patient evaluations of pain intensity, pain relief, and global assessments were recorded.For total pain relief over 6 hours (primary end point), rofecoxib was superior to codeine/acetaminophen (15.5 vs 10.7; P.001). Rofecoxib was statistically significantly superior to codeine/acetaminophen with respect to TOPAR4, patient global assessment, peak pain relief, and duration of analgesic effect. Median onset of analgesia was similar for both drugs. The codeine/acetaminophen group had more patients with 1 or more adverse events.Rofecoxib provided superior analgesic efficacy compared with codeine/acetaminophen with fewer gastrointestinal and nervous system adverse events.

Objective : To describe the variability of the asthma phenotype in patients with mild persistent asthma enrolled in the Mild Asthma Montelukast versus Inhaled Corticosteroid (MIAMI) study. Methods : The variability of asthma rescue-free days, asthma symptoms, albuterol use, medical resource use, and exercise limitations among patients with documented mild persistent asthma was compared between the month before study enrollment and the last 2 weeks of the run-in period. Results : Patients eligible for randomization ( n =400), aged 15–85 years, exhibited symptoms (mean±sd) 3.6±1.3days/week, β -agonist use 3.5±1.3 days/week, and normal FEV 1 (94.0±9.9% predicted) during the last 2 weeks of the run-in period. In the year before enrollment, medical intervention for asthma flares was common: 38.5% made office visits, 15.8% had oral corticosteroids, and 8.3% required emergency room or hospitalized care. In the month before enrollment, 11.8% experienced daily symptoms, and 28.3% had limitations of normal activity. Patients with daily symptoms in the month before study enrollment, compared with those having less-than-daily symptoms, experienced fewer rescue-free days ( P =0.024) and had more days per week with symptoms ( P =0.008) and requiring albuterol ( P =0.048) during the run-in; FEV 1 was similar for both groups (93.1% vs. 94.2% predicted, respectively). Conclusion : Patients with mild persistent asthma reported a substantial disease burden in the year before enrollment. The asthma burden experienced by these patients both before and during the run-in period was of sufficient severity to support the recommendation that mild persistent asthma should be managed with daily controller therapy.

We conducted a multicenter, single-blind, randomized comparison of the immunogenicity and safety of three manufacturing-scale lots of 7.5 μg liquid Haemophilus influenzae type b polysaccharide- Neisseria meningitidis conjugate vaccine (PRP-OMPC) and a single lot of 15.0 μg lyophilized PRP-OMPC. A total of 908 infants were entered into the study. Each infant received two primary injections intramuscularly 2 months apart beginning at age 2–6 months and a booster injection at 12–15 months. Blood samples for serology were obtained before each injection and 1 month after the second and the booster dose. Immune responses were measured by radioimmunoassay. Approximately 80% of the infants achieved a titer >1.0 μg ml −1 after the second primary dose of all four lots tested; the geometric mean titer (GMT) was ca 3 μg ml −1 for each vaccine group. After the booster dose, more than 90% of infants from each vaccine group had a titer >1.0 μg ml −1 ; GMTs ranged from 8 to 10 μg ml −1 . No serious vaccine-associated adverse reactions were reported. Thus the 7.5 μg liquid PRP-OMPC vaccine was at least as immunogenic and well tolerated as the 15.0 μg lyophilized vaccine.

Background Some patients administered cholesterol-lowering therapies may experience an increase in the proportion of small LDL particles, which may be misinterpreted as a worsening of atherosclerotic coronary heart disease risk. This study assessed the lipid effects of adding ezetimibe to atorvastatin or doubling the atorvastatin dose on low-density lipoprotein cholesterol (LDL-C) levels (and the cholesterol content of LDL subclasses), LDL particle number (approximated by apolipoprotein B), and LDL particle size. This was a multicenter, double-blind, randomized, parallel-group study of hypercholesterolemic, high atherosclerotic coronary heart disease risk patients. After stabilization of atorvastatin 40 mg, 579 patients with LDL-C >70 mg/dL were randomized to 6 weeks of ezetimibe + atorvastatin 40 mg or atorvastatin 80 mg. Efficacy parameters included changes from baseline in LDL-C, apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL-C), and lipoprotein subclasses (Vertical Auto Profile II) and pattern for the overall population, as well as patient subgroups with baseline triglyceride levels Results Both treatments significantly reduced LDL-C (and the cholesterol content of most LDL subfractions [LDL1-4]) apolipoprotein B, non-HDL-C levels, but did not reduce the proportion of smaller, more dense LDL particles; in fact, the proportion of Pattern B was numerically increased. Results were generally similar in patients with triglyceride levels Conclusions When assessing the effects of escalating cholesterol-lowering therapy, effects upon Pattern B alone to assess coronary heart disease risk may be misleading when interpreted without considerations of other lipid effects, such as reductions in LDL-C, atherogenic lipoprotein particle concentration, and non-HDL-C levels. Trial Registration (Registered at clinicaltrials.gov: Clinical trial # NCT00276484)

Rationale To compare the bronchodilator response to albuterol after a standard exercise challenge in patients receiving montelukast (M) or salmeterol (S) added to low-dose fluticasone (F). Methods Randomized, double-blind multicenter study. Patients with asthma (N=91, ages 15–60) receiving F (110 μg twice daily) who remained symptomatic and had a history of exercise-induced bronchoconstriction (EIB) were randomized to addition of M (10 mg) or S (42 μg BID) for 4 weeks. At weeks 1 and 4, patients exercised on a treadmill for 6 minutes at near-maximum heart rate; at 15 and 45 minutes after exercise, patients received 180 μg albuterol by inhalation. Serial spirometry was performed both before and after albuterol administration. FEV1 was expressed as the percent change from pre-exercise baseline. Results Baseline pre-exercise FEV1 percent predicted was 81.3 ± 1.5% in the M+F group and 78.9 ± 1.7% in the S+F group. Before treatment, patients in both groups had a significant increase in FEV1 in response to post-exercise albuterol (M+F: 11.9 ± 1.2%; S+F: 14.5 ± 1.6%). After 4 weeks, only S+F perceptibly improved pre-exercise FEV1 (7.5 ± 1.1% versus 2.1 ± 1.1%, p Conclusions The rescue response to albuterol after EIB in patients taking fluticasone is preserved with addition of montelukast but is significantly diminished with addition of salmeterol.