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Findling R.L.,University Hospitals Case Medical Center | Mckenna K.,University of California at Los Angeles | Earley W.R.,Forest Research Institute Inc. | Stankowski J.,ICON Clinical Research | Pathak S.,Astrazeneca
Journal of Child and Adolescent Psychopharmacology | Year: 2012

Objective: The purpose of this study was to evaluate the efficacy and safety of acute quetiapine monotherapy in adolescents with schizophrenia. Methods: Patients ages 13-17 years with an American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) diagnosis of schizophrenia and a Positive and Negative Syndrome Scale (PANSS) total score ≥60 were randomized to 6 weeks of quetiapine (400 or 800mg/day) or placebo treatment. The primary efficacy measure was change in PANSS total score from baseline to day 42. Safety endpoints included adverse events and assessments of clinical chemistry values, suicidality, and extrapyramidal symptoms. Results: The intent-to-treat population included 220 patients. Least-squares mean change in PANSS total score from baseline to endpoint was -27.31 with quetiapine 400mg/day, -28.44 with quetiapine 800mg/day, and -19.15 with placebo (p=0.043 and 0.009 for quetiapine 400 and 800mg/day, respectively, vs. placebo; mixed-model, repeated-measures analysis). Several secondary efficacy outcomes, including Clinical Global Impressions-Improvement score, supported the primary outcome measure in demonstrating significantly greater improvement in quetiapine groups than in the placebo group. Mean changes in body weight at day 42 were 2.2kg and 1.8kg for quetiapine 400 and 800mg/day, respectively, and -0.4kg for placebo. Mean changes in certain clinical chemistry parameters, including total cholesterol and triglycerides, were numerically greater in the quetiapine groups than in the placebo group. Adverse events associated with quetiapine were mostly mild to moderate in intensity and were consistent with its known profile in adults with schizophrenia. Conclusions: In this 6-week study of adolescent patients, quetiapine at doses of 400 and 800mg/day provided significant improvements in symptoms associated with schizophrenia in adolescent patients, including the primary efficacy measure of PANSS total score change. Quetiapine was generally well tolerated with a profile broadly similar to that reported in adult and adolescent populations. Clinical trial registration information: Quetiapine Fumarate (SEROQUEL ™) Compared to Placebo in the Treatment of Adolescent Patients With Schizophrenia (ANCHOR 112). Available at: http://www.clinicaltrials.gov/ ct2/show/NCT00090324?term=quetiapine+112&rank=1 © Copyright 2012, Mary Ann Liebert, Inc. 2012.

Biek D.,Cerexa Inc. | Critchley I.A.,Cerexa Inc. | Riccobene T.A.,Forest Research Institute Inc. | Thye D.A.,Cerexa Inc.
Journal of Antimicrobial Chemotherapy | Year: 2010

Ceftaroline fosamil is a novel cephalosporin with broad-spectrum activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae, and common Gram-negative organisms. The activity of ceftaroline against MRSA is attributed to its ability to bind to penicillin-binding protein (PBP) 2a with high affinity and inhibit the biochemical activity of PBP 2a more efficiently than other presently available β-lactams. The activity of ceftaroline against MRSA and the β-haemolytic streptococci makes it an attractive monotherapy agent for the treatment of complicated skin and skin structure infections (cSSSIs). Recent profiling and surveillance studies have shown that ceftaroline is active against contemporary skin pathogens collected from US and European medical centres in 2008. The mean free drug %T>MIC (percentage of time the drug concentration remains above the MIC) needed for stasis ranged from 26% for S. aureus to 39% for S. pneumoniae in the murine thigh infection model. Pharmacokinetic and pharmacodynamic target attainment predictions for 600 mg of ceftaroline fosamil every 12 h showed that the mean %T>MICs for which plasma free-drug concentrations exceeded an MIC of 1 and 2 mg/L were 71% and 51% of the dosing interval, respectively. For a 40% T>MIC target, the predicted attainments for infections due to pathogens for which ceftaroline MICs were 1 or 2 mg/L were 100% and 90%, respectively. Clinical and microbiological successes of ceftaroline fosamil in treating cSSSIs were demonstrated in two Phase III clinical studies, in which 96.8% of all baseline cSSSI isolates from the microbiologically evaluable population were inhibited by ceftaroline at ≤2mg/L. Ceftaroline fosamil is a promising broad-spectrum agent for the treatment of cSSSIs. © The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

Kim H.,Forest Research Institute Inc. | Shults J.,University of Pennsylvania
Journal of Statistical Software | Year: 2010

Quasi-least squares (QLS) is an alternative computational approach for estimation of the correlation parameter in the framework of generalized estimating equations (GEE). QLS overcomes some limitations of GEE that were discussed in Crowder (1995). In addition, it allows for easier implementation of some correlation structures that are not available for GEE. We describe a user written SAS macro called %QLS, and demonstrate application of our macro using a clinical trial example for the comparison of two treatments for a common toenail infection. %QLS also computes the lower and upper boundaries of the correlation parameter for analysis of longitudinal binary data that were described by Prentice (1988). Furthermore, it displays a warning message if the Prentice constraints are violated. This warning is not provided in existing GEE software packages and other packages that were recently developed for application of QLS (in Stata, MATLAB, and R). %QLS allows for analysis of continuous, binary, or count data with one of the following working correlation structures: the first-order autoregressive, equicorrelated, Markov, or tri-diagonal structures.

Riccobene T.A.,Forest Research Institute Inc. | Rekeda L.,Cerexa Inc. | Rank D.,Cerexa Inc. | Llorens L.,Cerexa Inc.
Antimicrobial Agents and Chemotherapy | Year: 2013

A randomized, double-blind, placebo-controlled, 3-period crossover study was conducted in 54 healthy adults to assess the effect of ceftaroline fosamil on the corrected QT (QTc) interval. The QT interval, corrected for heart rate using an individual correction formula (QTcIb), was determined predose and at 1, 1.25, 1.5, 2, 4, 8, 12, and 24.5 h after intravenous dosing with a supratherapeutic dose (1,500 mg) of ceftaroline fosamil, 400 mg moxifloxacin (positive control), and placebo. The pharmacokinetic profile of ceftaroline was also evaluated. At each time point following ceftaroline fosamil administration, the upper limit of the 90% confidence interval (CI) for the placebo-corrected change from predose baseline in QTcIb (ΔΔQTcIb) was below 10 ms (maximum, 3.4 ms at 1.5 h after dosing), indicating an absence of clinically meaningful QTc increase. The lower limit of the 90% CI of ΔΔQTcIb for moxifloxacin versus placebo was greater than 5 ms at 5 time points (maximum, 12.8 ms at 1 h after dosing), demonstrating assay sensitivity. There was no apparent correlation between ceftaroline plasma concentrations and ΔΔQTcIb. The supratherapeutic dose of ceftaroline fosamil (1,500 mg) resulted in substantially greater systemic exposure to ceftaroline than previously observed with standard therapeutic doses. Ceftaroline fosamil was well tolerated after a single 1,500-mg intravenous dose, and no clinically meaningful abnormalities in laboratory values or vital signs were observed. Copyright © 2013, American Society for Microbiology. All Rights Reserved.

Riccobene T.A.,Forest Research Institute Inc. | Su S.F.,Forest Research Institute Inc. | Rank D.,Cerexa Inc.
Antimicrobial Agents and Chemotherapy | Year: 2013

This study was conducted to determine the safety, tolerability, and pharmacokinetics of intravenous doses of ceftaroline fosamil administered in combination with the novel non-β-lactam β-lactamase inhibitor avibactam in healthy adults. In the single-dose, open-label arm, 12 subjects received single 1-h intravenous infusions of ceftaroline fosamil alone (600 mg), avibactam alone (600 mg), and ceftaroline fosamil in combination with avibactam (600/600 mg) separated by 5-day washout periods. In the multiple-dose, placebo-controlled, double-blind arm, 48 subjects received intravenous infusions of ceftaroline fosamil/avibactam at 600/600 mg every 12 h (q12h), 400/400 mg q8h, 900/900 mg q12h, 600/600 mg q8h, or placebo for 10 days. Ceftaroline and avibactam levels in plasma and urine were measured by liquid chromatography coupled with tandem mass spectrometry. No significant differences in systemic exposure of ceftaroline or avibactam were observed when the drugs were administered alone versus concomitantly, indicating that there was no apparent pharmacokinetic interaction between ceftaroline fosamil and avibactam administered as a single dose. No appreciable accumulation of either drug occurred with multiple intravenous doses of ceftaroline fosamil/avibactam, and pharmacokinetic parameters for ceftaroline and avibactam were similar on days 1 and 10. Infusions of ceftaroline fosamil/avibactam were well tolerated at total daily doses of up to 1,800 mg of each compound, and all adverse events (AEs) were mild to moderate in severity. Infusion-site reactions were the most common AEs reported with multiple dosing. The pharmacokinetic and safety profiles of ceftaroline fosamil/avibactam demonstrate that the 2 drugs can be administered concomitantly to provide an important broad-spectrum antimicrobial treatment option. Copyright © 2013, American Society for Microbiology.

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