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1.
Bioanalysis ; 5(14): 1765-74, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23862708

ABSTRACT

BACKGROUND: The Gyrolab™ workstation benefits from fully automated transfer of reagents and samples originating from a storage microplate onto a compact disc containing solid-phase microstructures composed of a 15 nl streptavidin-derivitized bead bed. RESULTS: This paper describes the development, full validation and use of the method in a regulated environment to measure a humanized bispecific monoclonal antibody-domain antibody (GSK-A) molecule using the Gyrolab immunoassay system in cynomolgus nonhuman primate plasma ranging from 5 to 250 µg/ml. The method was subsequently used in support of the TK portion of a regulated preclinical study in monkeys. CONCLUSION: The Gyrolab immunoassay system proved to be a viable alternative to traditional immunoassays and was used to support a regulated preclinical TK study. The speed of analysis that the Gyrolab provides was beneficial in meeting timelines to complete this project as multiple assays and repeat sample analysis could be completed in the same day.


Subject(s)
Automation , Immunoassay/methods , Animals , Macaca fascicularis , Reference Standards , Reproducibility of Results
2.
PLoS One ; 6(8): e23570, 2011.
Article in English | MEDLINE | ID: mdl-21887274

ABSTRACT

BACKGROUND: The cardioprotective effects of glucagon-like peptide-1 (GLP-1) and analogs have been previously reported. We tested the hypothesis that albiglutide, a novel long half-life analog of GLP-1, may protect the heart against I/R injury by increasing carbohydrate utilization and improving cardiac energetic efficiency. METHODS/PRINCIPAL FINDINGS: Sprague-Dawley rats were treated with albiglutide and subjected to 30 min myocardial ischemia followed by 24 h reperfusion. Left ventricle infarct size, hemodynamics, function and energetics were determined. In addition, cardiac glucose disposal, carbohydrate metabolism and metabolic gene expression were assessed. Albiglutide significantly reduced infarct size and concomitantly improved post-ischemic hemodynamics, cardiac function and energetic parameters. Albiglutide markedly increased both in vivo and ex vivo cardiac glucose uptake while reducing lactate efflux. Analysis of metabolic substrate utilization directly in the heart showed that albiglutide increased the relative carbohydrate versus fat oxidation which in part was due to an increase in both glucose and lactate oxidation. Metabolic gene expression analysis indicated upregulation of key glucose metabolism genes in the non-ischemic myocardium by albiglutide. CONCLUSION/SIGNIFICANCE: Albiglutide reduced myocardial infarct size and improved cardiac function and energetics following myocardial I/R injury. The observed benefits were associated with enhanced myocardial glucose uptake and a shift toward a more energetically favorable substrate metabolism by increasing both glucose and lactate oxidation. These findings suggest that albiglutide may have direct therapeutic potential for improving cardiac energetics and function.


Subject(s)
Cardiotonic Agents/pharmacology , Glucagon-Like Peptide 1/analogs & derivatives , Myocardial Reperfusion Injury/prevention & control , Myocardium/metabolism , Animals , Blood Glucose/metabolism , Body Weight/drug effects , Cyclic AMP/metabolism , Energy Metabolism/drug effects , Feeding Behavior/drug effects , Glucagon-Like Peptide 1/administration & dosage , Glucagon-Like Peptide 1/blood , Glucagon-Like Peptide 1/pharmacology , Heart , Heart Function Tests , Hemodynamics/drug effects , In Vitro Techniques , Insulin/blood , Lactic Acid/blood , Male , Metabolic Networks and Pathways/drug effects , Metabolic Networks and Pathways/genetics , Myocardial Infarction/complications , Myocardial Infarction/pathology , Myocardial Infarction/physiopathology , Myocardial Reperfusion Injury/complications , Myocardial Reperfusion Injury/physiopathology , Principal Component Analysis , Rats , Rats, Sprague-Dawley , Transcription, Genetic/drug effects
3.
Bioanalysis ; 2(9): 1597-608, 2010 Sep.
Article in English | MEDLINE | ID: mdl-21083288

ABSTRACT

BACKGROUND: Domain antibodies (dAbs; ∼10-15 kDa) are made up of the variable heavy chain or the variable light chain of the antibody structure, and retain binding capability. dAbs have proved difficult to detect in plasma using immunoassay without specific antibodies raised against the dAb. RESULTS: A sensitive and selective UPLC-MS/MS method for the absolute quantification of a dAb in monkey plasma was developed (range: 1 to 500 ng/ml) without the need for a specific capture antibody. This method was used to analyze pharmacokinetic studies early on in drug development. Furthermore, an immunoassay was developed and the pharmacokinetic samples were reanalyzed. CONCLUSION: The two assays show good correlation (r(2) = 0.92), giving confidence in using either method for quantification of the dAb.


Subject(s)
Blood Chemical Analysis/methods , Chromatography, High Pressure Liquid/methods , Immunoassay/methods , Immunoglobulin Fragments/blood , Tandem Mass Spectrometry/methods , Administration, Inhalation , Animals , Immunoglobulin Fragments/administration & dosage , Immunoglobulin Fragments/metabolism , Immunoglobulin Fragments/therapeutic use , Immunoglobulin G/chemistry , Immunoglobulin G/immunology , Injections, Intravenous , Macaca fascicularis , Trypsin/metabolism
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