Steven H. Wong

Effects of citalopram on worry and brain activation in patients with generalized anxiety disorder

The effects of auditory statements describing a personal worry on brain activation as measured by functional magnetic resonance imaging were examined in patients with generalized anxiety disorder (GAD) before and after anxiety reduction with citalopram. Six patients were imaged while listening to verbal descriptions of a personal worry or a neutral statement before treatment with citalopram and after 7 weeks of treatment. Pre-post drug analyses showed treatment with citalopram reduced self-reported anxiety and reduced BOLD responses to a pathology-specific worry and a neutral stimulus. After treatment, worry sentences, compared to neutral statements, elicit reduced BOLD responses in prefrontal regions, the striatum, insula and paralimbic regions. In addition, contrasts before and after treatment revealed reductions in the differential response that existed between worry and neutral statements. Overall reduction of BOLD response was most prominent during neutral statements, particularly in the left hemisphere. These findings support the clinical impression that GAD patients overreact to both pathology-specific and non-specific cues and that the reduction of anxiety attenuates the response to both types of cues.

Therapeutic drug monitoring for immunosuppressants.

BACKGROUND Immunosuppressants have significantly increased patient survival, e.g. in renal transplant up to 90% for the first year. METHODS Four immunosuppressants are used for clinical applications in the United States: cyclosporine (CsA) (Sandimmune and Neoral), FK 506-tacrolimus (ProGraf), mycophenolic mofetil (CellCept)--the prodrug for the mycophenolic acid (MPA), and rapamycin (RAPA) (Sirolimus). For CsA and FK 506, the rationale for monitoring is due to the variable pharmacokinetics, acute infection, dosage adjustment, non-compliance check, and for long-term maintenance therapy. Targeted whole blood concentrations ranges are: for CsA, 100-400 ng/ml depending on the methods, therapy and organs; and for FK 506, 5-20 ng/ml. For MPA, drug bioavailability--the plasma area-under-curve up to 12 h of 32.2-60.6 mg h/l was correlated to the biopsy-proven rejection rate of <10%. Monitoring is advocated for liver and renal transplants, for pediatrics, and for checking for non-compliance. RAPA monitoring is useful to check for variable pharmacokinetics, for non-compliance and others. The therapeutic range is tentatively targeted for 5-15 ng/ml. Monitoring methodologies are: for CsA, immunoassays such as fluorescence polarization immunoassay, and liquid chromatography (LC); for FK 506, microparticle enzyme immunoassay (MEIA); for MPA, enzyme multiplied immunoassay and LC; and for RAPA, MEIA, LC and LC-mass spectrometry. Proficiency survey programs for CsA and FK 506 are available from the US and Europe. CONCLUSIONS Monitoring of immunosuppressants has become an essential adjunct to the drug therapy for organ transplant patients.

Pharmacogenomic genotyping methodologies

Abstract “Personalized medicine” based on an individual’s genetic makeup is slowly becoming a reality as pharmacogenomics moves from the research setting to the clinical laboratory. Concordance studies between genotype and phenotype have shown that inherited mutations in several key drug-metabolizing enzymes, such as cytochrome P450 (CYP) 2D6, 2C9, and 2C19, result in several distinct phenotypes that lead to different individual responses following drug administration. One of the major driving forces behind pharmacogenomics and its ability to be used effectively are the technologies that are available. A beneficial genotyping test must identify most or all of the mutations that have a significant impact on the expression or function of drug-metabolizing enzymes, transporter proteins, and/or drug receptors. Selection of the appropriate technology will be based on several issues, including prior knowledge of the mutation/polymorphism, sensitivity/specificity, sample requirements, and cost. Since the future volume of pharmacogenomic testing is anticipated to be large, automation of pharmacogenomics will also become increasingly important. This paper provides an overview of current technologies available for assessing polymorphisms on a small- to large-scale basis.

From personalized medicine to personalized justice: the promises of translational pharmacogenomics in the justice system.

Enabled by Pharmacogenomics (PGx), molecular imaging, and other molecular biomarkers, personalized medicine (PM) promises to optimize therapy while minimizing side effects. It may also dramatically impact the justice system in ways we are only beginning to understand.

Chapter 22 Pharmacogenomics for forensic toxicology in enabling personalized medicine

Publisher Summary This chapter discusses pharmacogenomics for forensic toxicology in enabling personalized medicine. With the completion of the human genome project, one of the most tangible benefits is the emerging practice of pharmacogenomics as a part of genomic and personalized medicine. While pharmacogenomics and pharmacogenetics are currently used interchangeably, pharmacogenetics is readily defined as the study of the genetic effect—for example, single nucleotide polymorphism (SNP)—on an individuals ability to metabolize a drug or compound, whereas pharmacogenomics is concerned with the whole genome effect on drug metabolism and efficacy. Pharmacogenomic biomarker, in combination with well-accepted biomarkers such as therapeutic drug monitoring and other functional testing, emerging proteomic biomarkers and possibly molecular imaging, enables personalized medicine. The combination identifies the right patient, with the right diagnosis/treatment, matching with the right drug, the right dose, and at the right time, thus achieving clinical efficacy with no or minimized toxicity.

Pharmacogenetics in Clinical and Forensic Toxicology: Opioid Overdoses and Deaths

Factors considered in the observed variability in drug response within a population are intrinsic, extrinsic, or a combination of both. The intrinsic factors are differences in the demographics of a given individual (e.g., age or gender), disease or physical condition (e.g., renal function or BMI), and pharmacogenetics (see below). The extrinsic factors are composed of environmental factors (e.g., diet) as well as drug interactions or polypharmacy.

Chapter 10 Enantioselective liquid chromatographic analysis of drugs in forensic science

Publisher Summary This chapter describes the recent scientific and technical advances, and the current understanding of the principles and mechanisms in enantioselective liquid chromatographic separations. Chiral stationary phases and their potential applications to clinical forensic drug and metabolite analysis are discussed with a focus on the sample preparation and essential analytical parameters. Chiral pharmacology is gaining increasing recognition and relevance. Governmental agencies have encouraged the development of single isomers and racemic switch. Chiral analysis has witnessed rapid advances. With more than 100 chiral selectors, there is a steady infusion of new technologies, such as antibiotics chiral stationary phase (CSP) and other polymeric CSP. Amphetamines, methadone, non-steroidal anti-inflammatory drugs (NSAIDs), antidepressants, and selected anticancer drugs are of interest to clinical or forensic toxicology and therapeutic drug monitoring (TDM). There seems to be adequate selection for forensic toxicologists. Emerging from the increasing application of antibiotics bound CSP is the concept of the enantioselectivity complementarity. Perhaps, the limiting factor is the high cost of chiral columns. Further rapid advances in LC-MS and CE greatly enhance the sensitivity and specificity of enantiomeric analysis. Along with the rapid development in pharmacogenetics, enantiomeric analysis may contribute to the understanding of polymorphism in drug metabolism.