Analytical and Synthetic Chemistry Laboratories The need for analytical chemistry support for clinical studies arose because of increased appreciation of the importance of pharmacokinetics in understanding drug action in the late 1970s. Neal Benowitz had initiated pharmacokinetic studies of nicotine and opioids and Reese Jones initiated studies of cocaine pharmacokinetics and pharmacodynamics, largely supported by a P50 award. At that time, our analytical laboratory consisted of a chemist, two technicians and two gas chromatographs. Since, many projects requiring analytical chemistry support were initiated and our laboratory staff has grown from three to 14: Two PhD Research Chemists, nine Staff Research Associates and three Laboratory Assistants. Major equipment includes two gas chromatographs, two desktop GC-MS systems, two HPLCs, three triple-stage quadrupole LC-MS/MS systems, and two triple-stage quadrupole GC-MS/MS systems. Support for the laboratories comes from the P30 Center, ROIs and contracts. In recent years, our group has made extensive, and we believe innovative, use of stable isotope methodology. Stable isotope-labeled drugs, unlike those labeled with radioisotopes, are no more hazardous than unlabeled drugs. A stable isotope, such as the hydrogen isotope deuterium, incorporated into a drug molecule allows the labeled drug to be used as a tracer. This is a powerful tool in studies of pharmacokinetics and metabolism, frequently used in bioavailability studies. While the natural drug is administered by its usual route, such as oral, transdermal, or by smoking, the labeled drug is simultaneously administered intravenously for pharmacokinetic characterization. We have used this technique to determine nicotine intake from smoking (Benowitz et al. 1991a) and from smokeless tobacco (Jacob et al. 1999), bioavailability of transdermal nicotine (Benowitz et al. 1991b) and bioavailability of cocaine administered by various routes. We have used stable isotope methodology to study the metabolic disposition of cocaine and ethanol, including determination of the fractional conversion of cocaine to cocaethylene (Jacob et al. 1997;Everhart et al. 1998). Stable isotope methodology was used to determine the bioavailablity of intranasal and smoked methamphetamine (Harris et al. 2003). Our use of stable isotopes is continuing and expanding. We will be utilizing labeled frans-3'-hydroxycotinine to further our understanding of nicotine pharmacogenetics and to better understand the mechanism of racial differences in nicotine metabolism.. Cotinine-d4 and the metabolite ratio will be used to study the association of the rate of metabolism and development of addiction in adolescent light smokers (Mark Rubinstein, MD, CA140216). We have used stable isotope methodology to address questions unique to the drug abuse area. One such question was to determine whether intravenous nicotine replacement would suppress nicotine intake from smoking (Benowitz and Jacob 1990). This led to the conclusion that nicotine replacement medications such as transdermal patches (at that time undergoing premarketing clinical trials) would suppress smoking even if subjects were unable to quit entirely. We have used deuterium-labeled cocaine administration to study the time course of distribution of cocaine and its metabolite benzoylecgonine into human hair. For ethical reasons, these studies had to be carried out in cocaine abusers, and the use of labeled drug guaranteed that subsequent street cocaine use would not invalidate the results (Henderson et al. 1996). We are also using labeled nicotine to study the time course of accumulation of nicotine into hair and nails, which appear to be good long term biomarkers of nicotine exposure. Such studies require laboratories with synthetic and analytical chemists, and modern analytical instruments. Extensive use of mass spectrometry is necessary when using stable isotopes. Suitably labeled drugs or metabolites may not be commercially available, and our capability in synthetic organic chemistry has been needed to prepare stable-isotope labeled drugs, metabolites, and internal standards for clinical studies and assays. In this application, we are requesting support for laboratory, and administrative staff, and for instrumentation to maintain and enhance our analytical chemistry capabilities. Administrative Core Element A modest administrative core facility has been an important and cost effective element to maintain a coordinated clinical research support program. The unifying influence of a single office that answers or efficiently redirects procedural questions, helps prepare and distribute documents and papers, facilitates purchase of specialized equipment and supplies, manages ordering of controlled drugs, gives advice on human subject protection regulatory and procedural issues, assists in progress reports and offers guidance for journal manuscripts preparation, and acts as an interface with the UCSF accounting, purchasing and research administration bureaucracy has proved valuable. Much of those functions will continue as part of the Administrative Core. However since the time of our last competing renewal submission there have been significant positive changes in resources for researchers at UCSF, particulariy the establishment of a Clinical &Translational Science Institute (CTSI) that make advisable some significant reordering of priorities and certain functions of the Administrative Core. UCSF was one of the first academic institutions to become part of the NIH's national clinical &translational science consortium. The consortium goal, that the UCSF CTSI shares is to transform and enhance clinical and translational research to ensure that the best health solutions get to patients as quickly as possible. At UCSF, CTSI is a cross-campus institute. As a part of the National Institute of Health's CTSA network, UCSF's CTSI offers to the UCSF research community activities and an infrastructure for all the major areas identified as necessary to support clinical &translational research including for example, a Clinical Research Center (formally known as GCRCs) with 9 different sites, Biostatistics, Research Design and Ethics and Data Management consulting service, and Health Policy and Community Engagement programs. Many of members of our participating projects (Guydish, McCance-Katz for example) are involved with the CTSI integrated through direct studies, members of committees, participation in workshops and courses and/or as consultants. The CTSI and associated UCSF campus wide resources offer clinical researchers biostatistical consulting, data management and analysis resources far more sophisticated and complete than could ever be offered by a P30 Center. The same is true for training and consultation on research design, for example current courses available to all UCSF faculty and trainees offer courses biostatistics, clinical trials, informatics and database management, decision/cost analysis, translating practice into evidence and qualitative research methods. Consultation available on those and other matters of interest to researcher. So, with such Campus resources what additional resources can the P30 Administrative Core offer? Consultation through the CTSI and Division of Biostatistics at UCSF provides a useful resource. However, as part of P30 core support, additional modest, relative rapid, but more focused biostatistical consulting or initial consultations will be provided from a consultant (Dr. Delucchi, also a member of the CTSI/Biostatistics Division) experienced in dealing with the types of data and research design issues most common in drug dependence research. This would provide to investigators in participating projects more efficient and targeted data analysis and data base management advice. This would supplement Division of Biostatistics campus biostatistical consultation and outcomes research resources that offers excellent service but sometimes necessitates tracking down just the right consultant and spending a fair effort in bringing them up to speed on some of the particular research questions.
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