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West Lafayette, IN, United States

Scicinski J.,Radiorx Inc. | Oronsky B.,Radiorx Inc. | Cooper V.,BASi West Coast Operations | Taylor M.,NonClinical Safety Assessment | And 5 more authors.
Bioanalysis | Year: 2014

Background: Bioanalytical methods were required to study the novel anticancer drug, RRx-001 preclinically and for clinical pharmacokinetic analysis; however, RRx-001 quickly and completely disappeared on intravenous administration in preclinical species. Results: Quantification of RRx-001 directly or by derivatization was unsuccessful. On exposure to whole blood, RRx-001 formed the glutathione (GSH) adduct very rapidly, suggesting this metabolite as the bioanalyte. However, rapid enzymatic degradation in the blood matrix of RRx-001-GSH posed significant technical problems. Herein, we describe a novel and broadly applicable solution to stabilize GSH conjugates in blood samples by inhibiting the degrading enzyme. Liquid chromatography-tandem mass spectrometry methods for analysis of RRx-001-GSH in rat, dog and human plasma were developed and successfully validated to good laboratory practice standards. Conclusion: Extensive breakdown of RRx-001-GSH was effectively stopped by addition of the enzyme inhibitor, acivicin. The developed liquid chromatography-tandem mass spectrometry assay for RRx-001-GSH was validated for use in preclinical toxicology studies and the Phase I first-in-human clinical trial. © 2014 Future Science Ltd.

Marchant-Forde J.N.,U.S. Department of Agriculture | Matthews D.L.,Purdue University | Poletto R.,U.S. Department of Agriculture | Poletto R.,Purdue University | And 8 more authors.
Animal Welfare | Year: 2012

Minimising the effects of restraint and human interaction on the endocrine physiology of animals is essential for collection of accurate physiological measurements. Our objective was to compare stress-induced cortisol (CORT) and noradrenalin (NorA) responses in automated vs manual blood sampling in pigs. A total of 16 pigs (30 kg) were assigned to either: (i) automated blood sampling via an indwelling catheter using a novel-penning system called PigTurn® which detects the pig's rotational movement and responds by counter-rotating, allowing free movement while preventing catheter twisting; (ii) automated sampling while exposed to visual and auditory responses of manually sampled pigs; or (iii) manual sampling by jugular venipuncture while pigs were restrained in dorsal recumbency. During sampling of (i), personnel were not permitted in the room; samplings of (ii) and (iii) were performed simultaneously in the same room. Blood samples were collected every 20 min for 120 min and measured for CORT (ng ml-1 ) using mass spectrometry and NorA (pg ml -1) using High Performance Liquid Chromatography (HPLC). Effects of treatment and time were computed with mixed models adjusted by Tukey post hoc . CORT and NorA concentrations were lowest in group (i) followed by group (ii), which were not different. However, CORT and NorA levels in manually sampled animals (iii) were highest compared to automated methods (i) and (ii). Plasma concentrations across time were not different for CORT, but NorA concentration at time 0 min was higher than at 120 min. The presence of visual and auditory stimuli evoked by manual sampled animals did not affect non-handled pigs' responses. Restraint and manual sampling of pigs can be extremely stressful while the automated blood sampling of freely moving pigs, housed in the PigTurn® was significantly less stressful for the animals. © 2012 Universities Federation for Animal Welfare.

Sangster T.,Charles River Associates | Maltas J.,BASi | Struwe P.,Celerion | Hillier J.,Gen-Probe | And 27 more authors.
Bioanalysis | Year: 2012

The 5th Global CRO Council for Bioanalysis (GCC) meeting, held in Barcelona, Spain, in November 2011, provided a unique opportunity for CRO leaders to openly share opinions, perspectives and to agree on bioanalytical recommendations on incurred sample reproducibility in multi-analyte assays, regulation of quality assurance/bioanalytical consultants and regulatory requirements for GCP. © 2012 Future Science Ltd.

Rix P.J.,Seragon Pharmaceuticals | Vick A.,WIL Research | Attkins N.J.,Parexel International | Barker G.E.,Aires Pharmaceuticals | And 9 more authors.
Clinical Pharmacokinetics | Year: 2015

Introduction: The efficacy of nebulized sodium nitrite (AIR001) has been demonstrated in animal models of pulmonary arterial hypertension (PAH), but it was not known if inhaled nitrite would be well tolerated in human subjects at exposure levels associated with efficacy in these models.Methods: Inhaled nebulized sodium nitrite was assessed in three independent studies in a total of 82 healthy male and female subjects. Study objectives included determination of the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) under normal and mildly hypoxic conditions, and following co-administration with steady-state sildenafil, assessment of nitrite pharmacokinetics, and evaluation of the fraction exhaled nitric oxide (FENO) and concentrations of iron-nitrosyl hemoglobin (Hb(Fe)-NO) and S-nitrosothiols (R-SNO) as biomarkers of local and systemic NO exposure, respectively.Results: Nebulized sodium nitrite was well tolerated following 6 days of every 8 h administration up to 90 mg, producing significant increases in circulating Hb(Fe)-NO, R-SNO, and FENO. Pulmonary absorption of nitrite was rapid and complete, and plasma exposure dose was proportional through the MTD dosage level of 90 mg, without accumulation following repeated inhalation. At higher dosage levels, DLTs were orthostasis (observed at 120 mg) and hypotension with tachycardia (at 176 mg), but venous methemoglobin did not exceed 3.0 % at any time in any subject. Neither the tolerability nor pharmacokinetics of nitrite was impacted by conditions of mild hypoxia, or co-administration with sildenafil, supporting the safe use of inhaled nitrite in the clinical setting of PAH.Conclusion: On the basis of these results, nebulized sodium nitrite (AIR001) has been advanced into randomized trials in PAH patients. © 2014, The Author(s).

Lowes S.,Advion BioServices Inc. | Jersey J.,Agilux Laboratories | Shoup R.,AIT Bioscience | Garofolo F.,Algorithme Pharma Inc. | And 40 more authors.
Bioanalysis | Year: 2011

The Global CRO Council (GCC) for Bioanalysis was formed in an effort to bring together many CRO leaders to openly discuss bioanalysis and the regulatory challenges unique to the outsourcing industry. © 2011 Future Science Ltd.

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