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Princeton, NJ, United States

Covance Inc. with headquarters in Princeton, New Jersey, is a contract research organization providing drug development and animal testing services. According to its website, it is one of the largest companies of its kind in the world, with annual revenues of over $2 billion, and over 11,000 employees in more than 60 countries. It claims to provide the world's largest central laboratory network. It became a publicly traded company after being spun off by Corning Incorporated in 1996. In 2011 it was listed as one of the top 100 employers by the Diversity Employers Magazine.Under the name Covance Research Products Inc., based in Denver, Pennsylvania, the company also deals in the import, breeding and sale of laboratory animals. It breeds dogs, rabbits, guinea pigs, non-human primates, and pigs, and runs the largest non-human primate laboratory in Germany. The company became the subject of controversy following allegations in 2003–2005 by the British Union for the Abolition of Vivisection and People for the Ethical Treatment of Animals that non-human primates were being abused in its laboratories in Germany and the United States. No violations of the law were found by the authorities in the first case, and a small fine was levied in the second. In response, the company drew up a new welfare code to guide its treatment of laboratory animals.On November 3rd, 2014, Labcorp announced it would be purchasing Covance for $6.1bn. Wikipedia.

At present it is necessary to use animals to generate toxicokinetic data as part of preclinical safety studies. However, ethical standards require animal use to be carefully monitored and the principles of the 3Rs: replacement, reduction and refinement, to be considered and applied. Use of dried blood spot (DBS) samples, typically 10 to 20 μl, rather than the larger blood volumes required to obtain plasma samples, fully embraces the latter two principles of reduction and refinement. The use of DBS sampling enables the number of rodents per study to be reduced whilst also refining the way blood samples are taken from both rodents and non-rodents. The recent changes to the European Directive on the protection of animals used for scientific purposes favor DBS sampling becoming the standard for generation of toxicokinetic data, and imply that pharmaceutical companies will have to justify why plasma samples (and therefore larger blood volumes) are required for bioanalysis. Use of DBS samples has been, and is being, discussed widely within the pharmaceutical industry as the move away from taking large blood volumes becomes inevitable. © 2011 Future Science Ltd. Source

Baldrick P.,Covance
Regulatory Toxicology and Pharmacology

Interest in use of the polysaccharide chitosan as a pharmaceutical excipient by different dose routes and for a number of applications is not new but it still does not appear to be present in any marketed drugs. Including a novel excipient in a new drug formulation requires a number of safety considerations. Review of the published literature showed that chitosan has low oral toxicity and local tolerance potential supporting use in non-parenteral formulations. Prior human oral exposure has occurred through use of chitosan dietary supplements and food additive, medical device and cosmetic applications. Although systemic exposure to parent chitosan may be limited (due to digestion in the gastrointestinal tract), any that is absorbed will likely undergo enzyme degradation to naturally occurring glucosamine, and N-acetylglucosamine, its copolymers, which are excreted or used in the amino sugar pool. Chitosan has local biological activity in the form of haemostatic action and, together with its ability to activate macrophages and cause cytokine stimulation (which has resulted in interest in medical device and wound healing applications), may result in a more careful assessment of its safety as a parenteral excipient. © 2009 Elsevier Inc. All rights reserved. Source

An AOAC expert review panel (ERP) approved First Action Official MethodsSM on October 2, 2012, for determining iodine, pantothenic acid, carnitine, fatty acids, vitamins C and E, and choline in infant formula and adult/pediatric nutritional formula. The AOAC expert review panel (ERP) approved the First Action Official MethodsSM to support the Stakeholder Panel on Infant Formula and Adult Nutritionals (SPIFAN) initiative. Methods were also introduced for vitamins A and D and inositol for which AOAC had First Action methods. The internal standard was introduced for additional support and the ERP approved the method as AOAC Official Method 2012.14. AOAC Official Method 2012.15 stated that total iodine using inductively coupled plasma-mass spectrometry (ICP-MS) involved a unique sample digestion with potassium hydroxide solution in an oven or use of an open-vessel microwave system. The method was validated by performing experiments to determine precision, accuracy, linearity, and specificity. Source

Murck H.,Covance | Murck H.,University of Marburg
Journal of Psychiatric Research

The glutamatergic mechanism of antidepressant treatments is now in the center of research to overcome the limitations of monoamine-based approaches. There are several unresolved issues. For the action of the model compound, ketamine, NMDA-receptor block, AMPA-receptor activation and BDNF release appear to be involved in a mechanism, which leads to synaptic sprouting and strengthened synaptic connections. The link to the pathophysiology of depression is not clear. An overlooked connection is the role of magnesium, which acts as physiological NMDA-receptor antagonist: 1. There is overlap between the actions of ketamine with that of high doses of magnesium in animal models, finally leading to synaptic sprouting. 2. Magnesium and ketamine lead to synaptic strengthening, as measured by an increase in slow wave sleep in humans. 3. Pathophysiological mechanisms, which have been identified as risk factors for depression, lead to a reduction of (intracellular) magnesium. These are neuroendocrine changes (increased cortisol and aldosterone) and diabetes mellitus as well as Mg2+ deficiency. 4. Patients with therapy refractory depression appear to have lower CNS Mg2+ levels in comparison to health controls. 5. Experimental Mg2+ depletion leads to depression- and anxiety like behavior in animal models. 6. Ketamine, directly or indirectly via non-NMDA glutamate receptor activation, acts to increase brain Mg2+ levels. Similar effects have been observed with other classes of antidepressants. 7. Depressed patients with low Mg2+ levels tend to be therapy refractory. Accordingly, administration of Mg2+ either alone or in combination with standard antidepressants acts synergistically on depression like behavior in animal models. Conclusion: On the basis of the potential pathophysiological role of Mg2+-regulation, it may be possible to predict the action of ketamine and of related compounds based on Mg2+ levels. Furthermore, screening for compounds to increase neuronal Mg2+ concentration could be a promising instrument to identify new classes of antidepressants. Overall, any discussion of the glutamatergic system in affective disorders should consider the role of Mg2+. © 2013 Elsevier Ltd. Source

Insulin analogues represent a major and growing class of biotherapeutics, and their quantitation is an important focus of commercial and public effort across a number of different fields. As LC-MS has developed, it has become an increasingly practicable and desirable alternative to ligand-binding-based approaches for quantitation of this class of compounds. The sensitivity challenge of measuring trace levels of this large peptide molecule in a protein-containing matrix is considerable; however, different approaches to detection, extraction and separation are described to overcome this challenge, including immunoaffinity capture, SPE and low-flow HPLC. Considerations such as bioanalytical assay acceptance criteria and antidrug antibody effects during drug development are included, alongside descriptions of recent sports doping and clinical applications. Factors affecting the correlation and agreement of MS with biological ligand-binding methods are discussed, with ways to anticipate and appreciate differences between the values derived from each technique. The 'future perspective' section discusses the likely trend towards MS-based analysis for these compounds and the impact of HRMS. A high degree of scientific creativity, combined with science-defined regulatory approaches that define suitable validation criteria, will be needed to meet the demanding requirements for high-throughput analysis of insulin by LC-MS. © 2013 Future Science Ltd. Source

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