Prospective observational study of early respiratory management in preterm neonates less than 35 weeks of gestation.

BACKGROUND: Current guidelines for management of respiratory distress syndrome (RDS) recommend continuous positive airway pressure (CPAP) as the primary mode of respiratory support even in the most premature neonates, reserving endotracheal intubation (ETI) for rescue surfactant or respiratory failure. The incidence and timing of ETI in practice is poorly documented. METHODS: In 27 Level III NICUs in the US (n = 19), Canada (n = 3) and Poland (n = 5), demographics and baseline characteristics, respiratory support modalities including timing of ETI, administration of surfactant and caffeine/other methylxanthines, and neonatal morbidities were prospectively recorded in consecutive preterm neonates following written parental consent. Infants were divided into three groups according to gestational age (GA) at birth, namely 26-28, 29-32 and 33-34 weeks. Statistical comparisons between groups were done using Chi-Square tests. RESULTS: Of 2093 neonates (US = 1507, 254 Canada, 332 Poland), 378 (18%) were 26-28 weeks gestational age (GA), 835 (40%) were 29-32 weeks, and 880 (42%) were 33-34 weeks. Antenatal steroid use was 81% overall, and approximately 89% in neonates ≤32 weeks. RDS incidence and use of ventilatory or supplemental oxygen support were similar across all sites. CPAP was initiated in 43% of all infants, being highest in the 29-32-week group, with a lower proportion in other GA categories (p < 0.001). The overall rate of ETI was 74% for neonates 26-28 weeks (42% within 15 min of birth, 49% within 60 min, and 57% within 3 h), 33% for 29-32 weeks (13 16 and 21%, respectively), and 16% for 33-34 weeks (5, 6 and 8%, respectively). Overall intubation rates and timing were similar between countries in all GAs. Rates within each country varied widely, however. Across US sites, overall ETI rates in 26-28-week neonates were 30-60%, and ETI within 15 min varied from 0 to 83%. Similar within 15-min variability was seen at Polish sites (22-67%) in this GA, and within all countries for 29-32 and 33-34-week neonates. CONCLUSION: Despite published guidelines for management of RDS, rate and timing of ETI varies widely, apparently unrelated to severity of illness. The impact of this variability on outcome is unknown but provides opportunities for further approaches which can avoid the need for ETI.

Talactoferrin in Severe Sepsis: Results From the Phase II/III Oral tAlactoferrin in Severe sepsIS Trial.

OBJECTIVE: Talactoferrin alfa is a recombinant form of the human glycoprotein, lactoferrin, which has been shown to have a wide range of effects on the immune system. This phase II/III clinical trial compared talactoferrin with placebo, in addition to standard of care, in patients with severe sepsis. DESIGN: Multicenter, randomized, placebo-controlled, phase II/III clinical study. SETTING: Seventy-seven centers in 10 countries. PATIENTS: Adult (> 18 yr) patients admitted to one of the participating centers with severe sepsis who were receiving antimicrobial therapy and able to take liquid medication by mouth or feeding tube. INTERVENTIONS: Patients were randomized to receive either talactoferrin (1.5 g, 15 mL) or placebo three times a day orally or by another enteral route for 28 days or until ICU discharge. MEASUREMENTS AND MAIN RESULTS: The study was terminated after 305 patients had been enrolled (153 talactoferrin and 152 placebo) because of futility and safety concerns identified by the Data Safety Monitoring Board. There were no significant differences between groups in baseline characteristics including age, sex, site of infection, and severity scores. Twenty-eight-day mortality was higher in talactoferrin-treated patients although this difference was not statistically significant (24.8% vs 17.8% placebo; p = 0.117). The difference was largely the result of differences in patients with shock (talactoferrin, 33/105 [31.4%] vs placebo, 21/104 [20.2%]; p = 0.064); no mortality difference was seen in patients without shock (talactoferrin, 5/48 [10.4%] vs placebo, 6/48 [12.5%]; p = 0.806). In-hospital (43/153 [28.1%] vs 27/152 [17.8%]; p = 0.037) and 3-month (46/153 [30.1%] vs 31/152 [20.4%]; p = 0.036) mortality rates were significantly higher in talactoferrin-treated patients than in patients in the placebo group. The occurrence of treatment-related adverse or serious adverse events was similar between groups. CONCLUSIONS: Administration of oral talactoferrin was not associated with reduced 28-day mortality in patients with severe sepsis and may even be harmful.

A placebo-controlled, double-blind, dose-escalation study to assess the safety, tolerability and pharmacokinetics/pharmacodynamics of single and multiple intravenous infusions of AZD9773 in patients with severe sepsis and septic shock.

INTRODUCTION: Tumor necrosis factor-alpha (TNF-α), an early mediator in the systemic inflammatory response to infection, is a potential therapeutic target in sepsis. The primary objective of this study was to determine the safety and tolerability of AZD9773, an ovine, polyclonal, anti-human TNF-α Fab preparation, in patients with severe sepsis. Secondary outcomes related to pharmacokinetic (PK) and pharmacodynamic (PD) parameters. METHODS: In this double-blind, placebo-controlled, multicenter Phase IIa study, patients were sequentially enrolled into five escalating-dose cohorts (single doses of 50 or 250 units/kg; multiple doses of 250 units/kg loading and 50 units/kg maintenance, 500 units/kg loading and 100 units/kg maintenance, or 750 units/kg loading and 250 units/kg maintenance). In each cohort, patients were randomized 2:1 to receive AZD9773 or placebo. RESULTS: Seventy patients received AZD9773 (n=47) or placebo (n=23). Baseline characteristics were similar across cohorts. Mean baseline APACHE score was 25.9. PK data demonstrated an approximately proportional increase in concentration with increasing dose and a terminal half-life of 20 hours. For the multiple-dose cohorts, serum TNF-α concentrations decreased to near-undetectable levels within two hours of commencing AZD9773 infusion. This suppression was maintained in most patients for the duration of treatment. AZD9773 was well tolerated. Most adverse events were of mild-to-moderate intensity and considered by the reporting investigator as unrelated to study treatment. CONCLUSIONS: The safety, PK and PD data support the continued evaluation of AZD9773 in larger Phase IIb/III studies.

Intravenous esomeprazole pharmacodynamics in critically ill patients.

OBJECTIVE: A widely held belief contends that food-induced proton pump activation is important for optimal proton pump inhibitor-induced inhibition of gastric acid secretion. This study was undertaken to assess intragastric acid control with intravenous (IV) esomeprazole in critically ill patients. RESEARCH DESIGN AND METHODS: This open-label, single-arm, exploratory trial was conducted at five university or regional hospital intensive care units in the US. Adult patients admitted to an intensive care unit who required mechanical ventilation and had at least one additional risk factor for stress-induced ulcer received twice-daily IV esomeprazole 40 mg for 48 hours and could continue for another 24 hours if no prepyloric enteral feedings were planned. CLINICAL TRIAL REGISTRATION: D9612L00107; ClinicalTrials.gov Identifier NCT00428701. MAIN OUTCOME MEASURES: The primary efficacy variable was the linear-interpolated percentage of time intragastric pH was > or =4 during 24-48 hours. Secondary efficacy variables included the interpolated percentage of time intragastric pH was > or =4 during 0-24, 0-48, and 48-72 hours, the percentage of gastric aspirates collected with pH > or =4 during 0-24, 24-48, 0-48, and 48-72 hours, and time to stable pH > or =4. Safety was assessed based on adverse events (AEs), physical examinations, vital signs, laboratory tests, and electrocardiograms. RESULTS: Forty-five patients were enrolled (one was excluded because of previous partial gastrectomy). Interpolated mean percentage time pH > or =4 was 88.8%, 80.7%, and 83.5% for 24-48, 0-24, and 0-48 hours, respectively. For 0-72 hours, > or =78% of gastric aspirates had pH > or =4. Median time to stable pH was 1 hour (95% confidence interval: 0.67, 2.00). Treatment was well tolerated, with no evidence of gastrointestinal bleeding. A total of 75 AEs occurred in 34 patients, none considered treatment related. CONCLUSIONS: In this noncontrolled exploratory study, twice-daily IV esomeprazole 40 mg rapidly decreased intragastric acidity and effectively maintained pH >/=4 during 0-72 hours in fasting, critically ill, mechanically ventilated patients at high risk for stress ulcers.

Evaluation of efficacy and safety of budesonide delivered via two dry powder inhalers.

BACKGROUND: The dry powder inhaler (DPI) device for budesonide inhalation powder 200 microg (DPI-A) was redesigned to improve dosing consistency and provide new features (budesonide inhalation powder 90 microg and 180 microg; DPI-B). OBJECTIVE: Two multicenter, parallel-group, double-blind, randomized, 12-week studies compared the efficacy and safety of budesonide delivered via each DPI versus placebo, and the systemic exposure of budesonide from each device. METHODS: Asthmatic adults with mild-to-moderate asthma (N = 621) and patients 6-17 years with mild asthma (N = 516) received budesonide DPI-B 360 microg or DPI-A 400 microg twice-daily (total daily dose 720 microg or 800 microg), budesonide DPI-B 180 microg or DPI-A 200 microg once daily (total daily dose 180 microg or 200 microg), or matching placebo. Change in forced expiratory volume in 1 second (FEV(1)) and secondary variables (asthma symptoms, beta(2)-adrenergic agonist use, peak expiratory flow [PEF], and withdrawals due to worsening asthma) versus placebo were measured. RESULTS: In both studies, FEV(1) significantly (p < 0.05) improved for all active treatments versus placebo except once-daily budesonide DPI-B 180 mug in adults. In the adult study, significantly (p < 0.05) greater improvements in all secondary variables occurred with all active treatments versus placebo. In the pediatric/adolescent study, improvements in AM/PM PEF were significantly (p or= 6 years with very mild asthma and adolescents and adults with mild-to-moderate asthma. The study is limited by the evaluation of only two doses for each product in both studies. Additionally, the studies were not designed to test equivalence or noninferiority between the active products. Pharmacokinetic characterization was limited because of the small sample sizes.

FEV1 performance among patients with acute asthma: results from a multicenter clinical trial.

OBJECTIVE: To determine the ability of patients seen for acute asthma exacerbations in the emergency department (ED) to perform good-quality FEV(1) measurements. METHODS: Investigators from 20 EDs were trained to perform spirometry testing as part of a clinical trial that included standardized equipment with special software-directed prompts. Spirometry was done on ED arrival and 30 min, 1 h, 2 h, and 4 h later, and during follow-up outpatient visits. MEASUREMENTS: Study performance criteria differed from American Thoracic Society (ATS) guidelines because of the population acuity and severity of illness as follows: ability to obtain acceptable FEV(1) measures (defined as two or more efforts with forced expiratory times >/= 2 s and time to peak flow < 120 ms or back-extrapolated volume < 5% of the FVC) and reproducibility criteria (two highest acceptable FEV(1) values within 10% of each other). RESULTS: Of the 620 patients (age range, 12 to 65 years), > 90% met study acceptability criteria on ED arrival and 74% met study reproducibility criteria. Mean initial FEV(1) was 38% of predicted. Spirometry quality improved over time; by 1 h, 90% of patients met study acceptability and reproducibility criteria. Patients with severe airway obstruction (FEV(1) < 25% of predicted) were initially less likely to meet quality goals, but this improved with time. The site was also an independent predictor of quality. CONCLUSION: When staff are well trained and prompt feedback regarding adequacy of efforts is given, modified ATS performance goals for FEV(1) tests can be met from most acutely ill adolescent and adult asthmatics, even within the first hour of evaluation and treatment for an asthma exacerbation.

Effect of rosuvastatin on warfarin pharmacodynamics and pharmacokinetics.

The effect of rosuvastatin on warfarin pharmacodynamics and pharmacokinetics was assessed in 2 trials. In trial A (a randomized, double-blind, 2-period crossover study), 18 healthy volunteers were given rosuvastatin 40 mg or placebo on demand (o.d.) for 10 days with 1 dose of warfarin 25 mg on day 7. In trial B (an open-label, 2-period study), 7 patients receiving warfarin therapy with stable international normalized ratio values between 2 and 3 were coadministered rosuvastatin 10 mg o.d. for up to 14 days, which increased to rosuvastatin 80 mg if the international normalized ratio values were <3 at the end of this period. The results indicated that rosuvastatin can enhance the anticoagulant effect of warfarin. The mechanism of this drug-drug interaction is unknown. Rosuvastatin had no effect on the total plasma concentrations of the warfarin enantiomers, but the free plasma fractions of the enantiomers were not measured. Appropriate monitoring of the international normalized ratio is indicated when this drug combination is coadministered.

Zafirlukast treatment for acute asthma: evaluation in a randomized, double-blind, multicenter trial.

CONTEXT: Acute asthma causes nearly 2 million hospital emergency department (ED) visits in the United States annually, and hospitalization after an ED visit and relapse after ED discharge are common. OBJECTIVE: To evaluate the adding of therapy with zafirlukast to standardized care for patients with acute asthma in the ED and a 28-day follow-up period. DESIGN AND PATIENTS: A total of 641 patients presenting to the ED with acute asthma were randomized to receive either single-dose zafirlukast, 160 mg (Z160) [162 patients], zafirlukast, 20 mg (Z20) [158 patients]), or placebo (321 patients) as adjunct treatment to standard care in this double-blind, multicenter trial. Assessments, including spirometry and symptom scores, were obtained before each albuterol treatment and at 4 h. Patients who were discharged from the ED after 4 h continued outpatient therapy over a 28-day period and received either Z20 bid (276 patients) or placebo (270 patients) in addition to prednisone, albuterol, and their previous asthma medications. FEV(1) was measured at clinic visits on days 10 and 28. Patients recorded outpatient clinical data twice daily on a home diary card. MAIN OUTCOME MEASURES: the effect of zafirlukast on relapse after ED discharge. Other assessments were the rate of extended care (ie, ED stay for > 4 h or hospitalization), FEV(1), and symptoms. RESULTS: At the end of the outpatient period, 65 of 276 patients (23.6%) treated with zafirlukast and 78 of 270 patients (28.9%) treated with placebo relapsed (p = 0.047; absolute reduction, 5.3%; relative reduction, 18.3%). At the end of the ED period, 16 of 162 patients (9.9%) treated with Z160, 26 of 158 patients (16.5%) treated with Z20, and 48 of 321 patients (15.0%) treated with placebo required extended care (p = 0.052; absolute reduction with Z160 compared to placebo, 5.1%; relative reduction, 34%). These findings were supported by a significant improvement in FEV(1) and dyspnea in the ED with the use of Z160 therapy, and by greater improvement in FEV(1) and symptoms during the outpatient period for patients treated with Z20. CONCLUSIONS: When added to standardized care, therapy with Z20 bid reduced the risk of relapse compared with placebo over a 28-day treatment period. One dose of Z160 in the ED also reduced the rate of extended care.

Rosuvastatin pharmacokinetics in heart transplant recipients administered an antirejection regimen including cyclosporine.

BACKGROUND: Cyclosporine (INN, ciclosporin) increases the systemic exposure of all statins. Therefore rosuvastatin pharmacokinetic parameters were assessed in an open-label trial involving stable heart transplant recipients (> or =6 months after transplant) on an antirejection regimen including cyclosporine. Rosuvastatin has been shown to be a substrate for the human liver transporter organic anion transporting polypeptide C (OATP-C). Inhibition of this transporter could increase plasma concentrations of rosuvastatin. Therefore the effect of cyclosporine on rosuvastatin uptake by cells expressing OATP-C was also examined. METHODS: Ten subjects were assessed while taking 10 mg rosuvastatin for 10 days; 5 of these were then assessed while taking 20 mg rosuvastatin for 10 days. Rosuvastatin steady-state area under the plasma concentration-time curve from time 0 to 24 hours [AUC(0-24)] and maximum observed plasma concentration (Cmax) were compared with values in controls (historical data from 21 healthy volunteers taking 10 mg rosuvastatin). Rosuvastatin uptake by OATP-C-transfected Xenopus oocytes was also studied by use of radiolabeled rosuvastatin with and without cyclosporine. RESULTS: In transplant recipients taking 10 mg rosuvastatin, geometric mean values and percent coefficient of variation for steady-state AUC(0-24) and Cmax were 284 ng. h/mL (31.3%) and 48.7 ng/mL (47.2%), respectively. In controls, these values were 40.1 ng. h/mL (39.4%) and 4.58 ng/mL (46.9%), respectively. Compared with control values, AUC(0-24) and Cmax were increased 7.1-fold and 10.6-fold, respectively, in transplant recipients. In transplant recipients taking 20 mg rosuvastatin, these parameters increased less than dose-proportionally. Rosuvastatin had no effect on cyclosporine blood concentrations. The in vitro results demonstrate that rosuvastatin is a good substrate for OATP-C-mediated hepatic uptake (association constant, 8.5 +/- 1.1 micromol/L) and that cyclosporine is an effective inhibitor of this process (50% inhibition constant, 2.2 +/- 0.4 micromol/L when the rosuvastatin concentration was 5 micromol/L). CONCLUSIONS: Rosuvastatin exposure was significantly increased in transplant recipients on an antirejection regimen including cyclosporine. Cyclosporine inhibition of OATP-C-mediated rosuvastatin hepatic uptake may be the mechanism of the drug-drug interaction. Coadministration of rosuvastatin with cyclosporine needs to be undertaken with caution.

The effect of rosuvastatin on oestrogen & progestin pharmacokinetics in healthy women taking an oral contraceptive.

AIMS: To assess the effect of rosuvastatin on oestrogen and progestin pharmacokinetics in women taking a commonly prescribed combination oral contraceptive steroid (OCS); the effect on endogenous hormones and the lipid profile was also assessed. METHODS: This open-label, nonrandomised trial consisted of 2 sequential menstrual cycles. Eighteen healthy female volunteers received OCS (Ortho Tri-Cyclen) on Days 1-21 and placebo OCS on Days 22-28 of Cycles A and B Rosuvastatin 40 mg was also given on Days 1-21 of Cycle B. RESULTS: Co-administration did not result in lower exposures to the exogenous oestrogen or progestin OCS components. Co-administration increased AUC[0-24] for ethinyl oestradiol (26%; 90% CI ratio 1.19-1.34), 17-desacetyl norgestimate (15%; 90% CI 1.10-1.20), and norgestrel (34%; 90% CI 1.25-1.43), and increased Cmax for ethinyl oestradiol (25%; 90% CI 1.17-1.33) and norgestrel (23%; 90% CI 1.14-1.33). The increases in exposure were attributed to a change in bioavailability rather than a decrease in clearance. Luteinizing and follicle-stimulating hormone concentrations were similar between cycles. There were no changes in the urinary excretion of cortisol and 6beta-hydroxycortisol. Rosuvastatin significantly decreased low-density lipoprotein cholesterol [-55%], total cholesterol [-27%], and triglycerides [-12%], and significantly increased high-density lipoprotein cholesterol[11%]. Co-administration was well tolerated. CONCLUSIONS: Rosuvastatin can be coadministered with OCS without decreasing OCS plasma concentrations, indicating that contraceptive efficacy should not be decreased. The results are consistent with an absence of induction of CYP3A4 by rosuvastatin. The expected substantial lipid-regulating effect was observed in this study, and there was no evidence of an altered lipid-regulating effect with OCS coadministration.

Rosuvastatin improves the atherogenic and atheroprotective lipid profiles in patients with hypertriglyceridemia.

BACKGROUND: We examined the effects of rosuvastatin treatment on triglyceride levels and lipid measures in a parallel-group multicenter trial (4522IL/0035) in patients with hypertriglyceridemia (Fredrickson Type IIb or IV). METHODS: After a 6-week dietary lead-in period while on a National Cholesterol Education Program step I diet, 156 patients with fasting triglyceride levels >/= 300 and < 800 mg/dl were randomized to 6 weeks of double-blinded treatment: once-daily rosuvastatin of 5, 10, 20, 40 or 80 mg or placebo. The primary end point was mean percentage change from baseline in total serum triglyceride levels at week 6 as determined by analysis of variance. RESULTS: Rosuvastatin at all doses produced significant mean reductions in triglycerides compared with placebo (-18 to -40 compared with +2.9%, P 5 mg. The occurrence of adverse events was generally low and not dose related, although some adverse events occurred more frequently in the rosuvastatin 80 mg group. CONCLUSIONS: Rosuvastatin reduced triglyceride levels and improved the overall atherogenic and atheroprotective lipid profiles in hypertriglyceridemic patients.

Comparative effects of rosuvastatin and atorvastatin across their dose ranges in patients with hypercholesterolemia and without active arterial disease.

The lipid-lowering effects of rosuvastatin and atorvastatin were determined across their dose ranges in a 6-week, randomized, double-blind trial. Three hundred seventy-four hypercholesterolemic patients with fasting low-density lipoprotein (LDL) cholesterol > or =160 but <250 mg/dl (> or =4.14 but <6.47 mmol/L) and fasting triglycerides <400 mg/dl (<4.52 mmol/L) and without active arterial disease within 3 months of entry received once-daily rosuvastatin (5, 10, 20, 40, or 80 mg [n = 209]) or atorvastatin (10, 20, 40, or 80 mg [n = 165]). The percentage decrease in plasma LDL cholesterol versus dose was log-linear for each drug, ranging from -46.6% to -61.9% for rosuvastatin 10 and 80 mg, compared with -38.2% to -53.5% for atorvastatin 10 and 80 mg. The dose curve for rosuvastatin yielded an 8.4% greater decrease in LDL cholesterol compared with atorvastatin at any given dose (p <0.001). Similarly greater decreases were observed for rosuvastatin across the dose range in total cholesterol (-4.9%), non-high-density lipoprotein (non-HDL) cholesterol (-7.0%), apolipoprotein B (-6.3%), and related ratios versus atorvastatin (all p <0.001). Because dose responses for HDL cholesterol, triglycerides, and apolipoprotein A-I were non-log-linear and nonparallel between the 2 drugs, percentage changes from baseline were compared at each dose. Significantly greater increases for rosuvastatin compared with atorvastatin were observed for HDL cholesterol at 40 and 80 mg, and for apolipoprotein A-I at 80 mg. Significantly greater triglyceride decreases were seen at 80 mg with atorvastatin over rosuvastatin. Both rosuvastatin and atorvastatin were well tolerated over 6 weeks.