Single-dose intravenous casopitant in combination with ondansetron and dexamethasone for the prevention of oxaliplatin-induced nausea and vomiting: A multicenter, randomized, double-blind, active-controlled, two arm, parallel group study
Hesketh P.J.,Lahey Clinic Medical Center |
Wright O.,1250 South Collegeville Road |
Rosati G.,S Carlo Hospital |
Russo M.,1250 South Collegeville Road |
And 6 more authors.
Supportive Care in Cancer | Year: 2012
Purpose The primary objective was to determine if a single dose of casopitant 90 mg added to ondansetron and dexamethasone would improve the control of chemotherapy-induced nausea and vomiting (CINV) over 0-120 h following initiation of oxaliplatin-based moderately emetic chemotherapy (MEC) compared to ondansetron and dexamethasone alone. Methods Patients with colorectal cancer received either casopitant or placebo intravenously (IV) added to ondansetron 8 mg bid oral on study days 1 to 3 and one dose of dexamethasone 8 mg IV given prior to starting the oxaliplatin on day 1. The primary endpoint was the percentage of subjects achieving complete response (CR; no vomiting/retching or use of rescue medication) during 120 h after initiation of chemotherapy in cycle 1. Results No difference in the rate of CR was noted in the casopitant group compared to the placebo group for the overall (placebo 85%, casopitant 86%, p=0.7273), acute (placebo 96%, casopitant 97%), or delayed phases (placebo 85%, casopitant 86%). The average area under curve (0-∞) of casopitant after a single 90-mg IV dose was 8,390 ng h/mL. At 24 h after casopitant 90-mg IV dosing, the plasma casopitant concentration was 24% lower than the values noted in prior studies with 150 mg oral administration, and the plasma exposure of the major metabolite (GSK525060) was 18% lower. Conclusions Addition of single-dose casopitant 90 mg IV did not improve the control of CINV at any time during 120 h following initiation of oxaliplatin-based MEC. Excellent control of CINV was achieved in this study population with the combination of ondansetron and dexamethasone alone. © 2011 Springer-Verlag.
Alder C.M.,Medicines Research Center |
Hayler J.D.,Medicines Research Center |
Redman A.M.,Moore Research |
Shukla L.,Medicines Research Center |
And 2 more authors.
Green Chemistry | Year: 2016
GlaxoSmithKline (GSK) has previously reported on the development of a GSK solvent guide, the incorporation of lifecycle impact and the expansion of the guide including a customisable version intended for posting in different business areas. This guide has recently been enhanced by: (1) adding 44 additional solvents, many of which have literature claims to be "green"; (2) adjusting the way in which multiple health, environment, safety, and waste categories are combined to reach a single composite score and colour assignment; (3) updating the data behind all scores, especially toxicology and health hazard assessment, and revising the methodology to reflect current guidelines and data. The full methodology behind this work is hereby shared. The new GSK Solvent Sustainability Guide enables GSK scientists to objectively assess solvents. It facilitates both comparison of individual sustainability criteria, and a composite score and colour for rank ordering, incorporating multiple facets of sustainability. © 2016 The Royal Society of Chemistry.
Disantostefano R.L.,Moore Research |
Hinds D.,1250 South Collegeville Road |
Van Le H.,Moore Research |
Van Le H.,Parexel International |
And 2 more authors.
Respiratory Medicine | Year: 2016
Background Current evidence suggests that blood eosinophil levels (Eos) are associated with chronic obstructive pulmonary disease (COPD) treatment response and natural history. This analysis investigated the relationship between Eos levels and clinical characteristics in a representative cohort of US subjects with spirometry-defined COPD. Methods Cross-sectional data from the National Health And Nutrition Examination Survey (NHANES 2007-2010) of subjects ≥40 years with spirometry-defined COPD and Eos data (n = 948) were analyzed. Differences in clinical characteristics by Eos level (≤2%, >2%) were compared using chi-square tests. Characteristics associated with Eos >2% were identified using multivariate logistic regression modeling. Characteristics associated with Eos >2% among subjects with normal lung function, plus other cut-points among the COPD population, were evaluated post hoc. Findings Most participants had Eos >2%; 70.7% with spirometry-defined COPD and 65.5% with normal lung function. Older age, male gender, and severe current asthma were significantly associated with Eos >2% in COPD subjects. The Eos ≤2% COPD group had higher reported rates of previous heart attack and anemia. Among participants with normal lung function, Eos >2% was associated with being male, being overweight/obese, older age, hay fever, and congestive heart failure. Interpretation In this large US-based cohort, Eos >2% was prevalent in participants with COPD and normal lung function. Among participants with COPD, Eos >2% was associated with specific characteristics including lower rates of some co-morbidities; however, the clinical implications and relationships between Eos levels, COPD mechanisms, and risk of outcomes require further evaluation. © 2016 The Authors.
Gottlieb H.E.,Bar - Ilan University |
Graczyk-Millbrandt G.,GSK |
Inglis G.G.A.,Medicines Research Center |
Nudelman A.,Bar - Ilan University |
And 5 more authors.
Green Chemistry | Year: 2016
Residual solvents often appear as nuisance signals in experimental NMR spectra, and many chemists turn to well-known literature sources to quickly identify such peaks. While these publications are very useful, they do not currently include many solvents exemplified in green chemistry-related literature. This work provides a single compiled reference for NMR chemical shifts of 80 solvents in each of 6 deuterated NMR solvents. The overall green chemistry assessments, as reached via the methodology of the GSK Solvent Sustainability Guide, are displayed on these charts. ©2016 The Royal Society of Chemistry.
Adams J.P.,Medicines Research Center |
Alder C.M.,Medicines Research Center |
Andrews I.,Medicines Research Center |
Bullion A.M.,GSK |
And 10 more authors.
Green Chemistry | Year: 2013
Reagent guides ranking commonly used reagents for 15 transformations have been developed to reduce the environmental impact of drug discovery and development. Reagents have been scored by a combination of health, safety and environmental risk phrases, life cycle analysis (where possible) and an assessment of the chemistry including considerations of atom efficiency, stoichiometry, work-up and other issues. Guides covering alkene reduction, amide formation, C-H bromination, C-H chlorination, deoxychlorination, epoxidation, ester formation, ether formation, fluorination, iodination, ketone reduction, nitro reduction, oxidation of alcohols to aldehydes and ketones, reductive amination and sulfur oxidation are shared, with an explanation of the methodology behind their generation. © 2013 The Royal Society of Chemistry.
PubMed | Respiratory Research & Development, Moore Research, 1250 South Collegeville Road and Parexel International
Type: | Journal: Respiratory medicine | Year: 2016
Current evidence suggests that blood eosinophil levels (Eos) are associated with chronic obstructive pulmonary disease (COPD) treatment response and natural history. This analysis investigated the relationship between Eos levels and clinical characteristics in a representative cohort of US subjects with spirometry-defined COPD.Cross-sectional data from the National Health And Nutrition Examination Survey (NHANES 2007-2010) of subjects 40 years with spirometry-defined COPD and Eos data (n = 948) were analyzed. Differences in clinical characteristics by Eos level ( 2%, > 2%) were compared using chi-square tests. Characteristics associated with Eos > 2% were identified using multivariate logistic regression modeling. Characteristics associated with Eos >2% among subjects with normal lung function, plus other cut-points among the COPD population, were evaluated post hoc.Most participants had Eos >2%; 70.7% with spirometry-defined COPD and 65.5% with normal lung function. Older age, male gender, and severe current asthma were significantly associated with Eos >2% in COPD subjects. The Eos 2% COPD group had higher reported rates of previous heart attack and anemia. Among participants with normal lung function, Eos > 2% was associated with being male, being overweight/obese, older age, hay fever, and congestive heart failure.In this large US-based cohort, Eos > 2% was prevalent in participants with COPD and normal lung function. Among participants with COPD, Eos > 2% was associated with specific characteristics including lower rates of some co-morbidities; however, the clinical implications and relationships between Eos levels, COPD mechanisms, and risk of outcomes require further evaluation.
Ma J.,Glaxosmithkline |
Martin J.D.,1250 South Collegeville Road |
Xue Y.,Glaxosmithkline |
Lor L.A.,1250 South Collegeville Road |
And 7 more authors.
Archives of Biochemistry and Biophysics | Year: 2010
USP7, also known as the hepes simplex virus associated ubiquitin-specific protease (HAUSP), deubiquitinates both mdm2 and p53, and plays an important role in regulating the level and activity of p53. Here, we report that deletion of the TRAF-like domain at the N-terminus of USP7, previously reported to contain the mdm2/p53 binding site, has no effect on USP7 mediated deubiquitination of Ubn-mdm2 and Ubn-p53. Amino acids 208-1102 were identified to be the minimal length of USP7 that retains proteolytic activity, similar to full length enzyme, towards not only a truncated model substrate Ub-AFC, but also Ubn-mdm2, Ubn-p53. In contrast, the catalytic domain of USP7 (amino acids 208-560) has 50-700 fold less proteolytic activity towards different substrates. Moreover, inhibition of the catalytic domain of USP7 by Ubal is also different from the full length or TRAF-like domain deleted proteins. Using glutathione pull-down methods, we demonstrate that the C-terminal domain of USP7 contains additional binding sites, a.a. 801-1050 and a.a. 880-1050 for mdm2 and p53, respectively. The additional USP7 binding site on mdm2 is mapped to be the C-terminal RING finger domain (a.a. 425-491). We propose that the C-terminal domain of USP7 is responsible for maintaining the active conformation for catalysis and inhibitor binding, and contains the prime side of the proteolytic active site. © 2010 Elsevier Inc.
Amonkar M.M.,1250 South Collegeville Road |
Chastek B.,Health Economic and Outcomes Research |
Samant N.,Health Economic and Outcomes Research |
Teitelbaum A.,Medical and Scientific Affairs
Journal of Medical Economics | Year: 2011
Background: Squamous cell carcinoma of the head and neck (SCCHN) places a high burden on society and poses complex challenges to healthcare providers. Methods: Retrospective claims-based analysis of commercially insured patients identified between 01-31-04 and 12-31-07 with diagnostic evidence of cancer of the lip, tongue, oral cavity, pharynx, or larynx who underwent surgical resection during identification period. Outcomes included treatment patterns, healthcare utilization, and costs. All study variables were analyzed descriptively. Results: Among the 1104 patients in the final study sample, 71.9% were male, with mean age 56.6 years. On average, patients were followed for 830 days (range of mean days: 805 for lip or tongue cancer to 847 for pharyngeal cancer). About half received radiation therapy during follow-up, whereas only 16.2% received chemotherapy. Patients with pharyngeal cancer were most likely to undergo chemotherapy. After their index surgery, 57.9% of patients had ≥1 inpatient stay, 44.9% had ≥1 ER visit, and all had ≥1 ambulatory visit. The percentage with ≥1 inpatient stay post-index was highest among patients with pharyngeal cancer (73.0%) and lowest in the laryngeal cancer cohort (49.5%). Mean number of hospitalized days, ER visits, and ambulatory visits was 0.45, 0.69, and 27.4, respectively, per-patient per-year. Overall, patients incurred ∼$94 million in cost following index surgery ($85,000 per-person, on average). Mean total healthcare cost was $34,450 per-patient per-year, the bulk of which comprised medical expenses ($32,401). The highest mean healthcare cost was incurred by the pharyngeal cancer cohort ($40,214). Conclusions: Patients with resected SCCHN incur substantial healthcare costs and have high utilization rates. Results of this analysis are primarily applicable to resected SCCHN in a managed-care setting, and therefore may not be generalizable to the entire US population. Furthermore, disease stage is an important factor impacting outcomes, but these analyses did not stratify patients according to disease stage. © 2011 Informa UK Ltd All rights reserved.
Pietrak B.,1250 South Collegeville Road |
Zhao H.,1250 South Collegeville Road |
Qi H.,1250 South Collegeville Road |
Quinn C.,1250 South Collegeville Road |
And 8 more authors.
Biochemistry | Year: 2011
Heterozygously expressed single-point mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2, respectively) render these dimeric enzymes capable of producing the novel metabolite R-hydroxyglutarate (αHG). Accumulation of αHG is used as a biomarker for a number of cancer types, helping to identify tumors with similar IDH mutations. With IDH1, it has been shown that one role of the mutation is to increase the rate of conversion from αKG to αHG. To improve our understanding of the function of this mutation, we have detailed the kinetics of the normal (isocitrate to αKG) and neomorphic (αKG to αHG) reactions, as well as the coupled conversion of isocitrate to αHG. We find that the mutant IDH1 is very efficient in this coupled reaction, with the ability to form αHG from isocitrate and NADP+. The wild type/wild type IDH1 is also able to catalyze this conversion, though it is much more sensitive to concentrations of isocitrate. This difference in behavior can be attributed to the competitive binding between isocitrate and αKG, which is made more favorable for αKG by the neomorphic mutation at arginine 132. Thus, each partial reaction in the heterodimer is functionally isolated from the other. To test whether there is a cooperative effect resulting from the two subunits being in a dimer, we selectively inactivated each subunit with a secondary mutation in the NADP/H binding site. We observed that the remaining, active subunit was unaffected in its associated activity, reinforcing the notion of each subunit being functionally independent. This was further demonstrated using a monomeric form of IDH from Azotobacter vinelandii, which can be shown to gain the same neomorphic reaction when a homologous mutation is introduced into that protein. © 2011 American Chemical Society.
Yu H.,1250 South Collegeville Road |
Moore M.L.,1250 South Collegeville Road |
Erhard K.,1250 South Collegeville Road |
Hardwicke M.A.,1250 South Collegeville Road |
And 10 more authors.
ACS Medicinal Chemistry Letters | Year: 2013
A series of novel [3a,4]dihydropyrazolo[1,5a]pyrimidines were identified, which were highly potent and selective inhibitors of PI3Kβ. The template afforded the opportunity to develop novel SAR for both the hinge-binding (R 3) and back-pocket (R4) substitutents. While cellular potency was relatively modest due to high protein binding, the series displayed low clearance in rat, mouse, and monkey. © 2013 American Chemical Society.