An update to returning genetic research results to individuals: perspectives of the industry pharmacogenomics working group.

The ease with which genotyping technologies generate tremendous amounts of data on research participants has been well chronicled, a feat that continues to become both faster and cheaper to perform. In parallel to these advances come additional ethical considerations and debates, one of which centers on providing individual research results and incidental findings back to research participants taking part in genetic research efforts. In 2006 the Industry Pharmacogenomics Working Group (I-PWG) offered some 'Points-to-Consider' on this topic within the context of the drug development process from those who are affiliated to pharmaceutical companies. Today many of these points remain applicable to the discussion but will be expanded upon in this updated viewpoint from the I-PWG. The exploratory nature of pharmacogenomic work in the pharmaceutical industry is discussed to provide context for why these results typically are not best suited for return. Operational challenges unique to this industry which cause barriers to returning this information are also explained.

Neurokinin 1 receptor antagonism as a possible therapy for alcoholism.

Alcohol dependence is a major public health challenge in need of new treatments. As alcoholism evolves, stress systems in the brain play an increasing role in motivating continued alcohol use and relapse. We investigated the role of the neurokinin 1 receptor (NK1R), a mediator of behavioral stress responses, in alcohol dependence and treatment. In preclinical studies, mice genetically deficient in NK1R showed a marked decrease in voluntary alcohol consumption and had an increased sensitivity to the sedative effects of alcohol. In a randomized controlled experimental study, we treated recently detoxified alcoholic inpatients with an NK1R antagonist (LY686017; n = 25) or placebo (n = 25). LY686017 suppressed spontaneous alcohol cravings, improved overall well-being, blunted cravings induced by a challenge procedure, and attenuated concomitant cortisol responses. Brain functional magnetic resonance imaging responses to affective stimuli likewise suggested beneficial LY686017 effects. Thus, as assessed by these surrogate markers of efficacy, NK1R antagonism warrants further investigation as a treatment in alcoholism.

Identifying pharmacodynamic protein markers of centrally active drugs in humans: a pilot study in a novel clinical model.

Recognizing specific protein changes in response to drug administration in humans has the potential for significant utility in clinical research. In spite of this, many methodological and practical questions related to assessing such changes are unanswered. We conducted a series of clinical studies to assess the feasibility of measuring changes in proteins related to drug administration using a mass-spectrometry proteomics technique capable of quantifying hundreds of proteins simultaneously in cerebrospinal fluid (CSF) and plasma. Initially, the normal variability of proteins in these compartments was characterized in 16 healthy volunteers over a 2-week period. Drug-associated changes were subsequently assessed in the plasma and CSF proteomes of 11 subjects given atomoxetine, which served as a selective, centrally active probe to test the model. Protein levels in the CSF and plasma were unchanged between visits in the normal variability study. In contrast, statistically significant changes were detected in the CSF protein pattern after drug treatment. These studies suggest that identification of changes in the CSF proteome associated with the administration of centrally active drugs is feasible, and may be of value in the development of new drugs, as well as broader clinical research.