Administrative Resource

分析和合成化学实验室 20 世纪 70 年代末，人们越来越认识到药代动力学在理解药物作用方面的重要性，因此临床研究需要分析化学支持。 Neal Benowitz 发起了尼古丁和阿片类药物的药代动力学研究，Reese Jones 发起了可卡因药代动力学和药效学的研究，这在很大程度上得到了 P50 奖项的支持。当时，我们的分析实验室由一名化学家、两名技术人员和两台气相色谱仪组成。此后，许多需要分析化学支持的项目启动，我们的实验室工作人员已从 3 名增加到 14 名：两名博士研究化学家、九名研究员和三名实验室助理。主要设备包括两台气相色谱仪、两台台式GC-MS系统、两台高效液相色谱仪、三台三级四极杆LC-MS/MS系统和两台三级四极杆GC-MS/MS系统。 对实验室的支持来自 P30 中心、ROI 和合同。 近年来，我们的团队广泛且创新地使用了稳定同位素方法。 与放射性同位素标记的药物不同，稳定同位素标记的药物并不比放射性同位素标记的药物更危险。 未贴标签的药物。将稳定同位素（例如氢同位素氘）掺入药物分子中，可以将标记的药物用作示踪剂。这是药代动力学和代谢研究的强大工具，经常用于生物利用度研究。天然药物通过常规途径给药，如口服、透皮或吸烟，而标记药物则同时静脉给药以进行药代动力学表征。我们使用这种技术来确定吸烟（Benowitz 等人，1991a）和无烟烟草（Jacob 等人，1999）的尼古丁摄入量、透皮尼古丁的生物利用度（Benowitz 等人，1991b）以及通过各种途径施用的可卡因的生物利用度。我们用过稳定的 研究可卡因和乙醇代谢处置的同位素方法，包括测定可卡因向可卡乙烯的转化分数（Jacob 等人，1997 年；Everhart 等人，1998 年）。稳定同位素方法用于确定鼻内和吸食甲基苯丙胺的生物利用度（Harris 等人，2003 年）。我们正在继续并扩大对稳定同位素的使用。我们将利用标记的反式-3'-羟基可替宁来进一步了解尼古丁药物遗传学，并更好地了解尼古丁代谢中种族差异的机制。可替宁-d4和代谢物比率将用于研究青少年轻度吸烟者的代谢率和成瘾发展之间的关系（Mark Rubinstein，医学博士，CA140216）。 我们使用稳定同位素方法来解决药物滥用领域特有的问题。其中一个问题是确定静脉注射尼古丁替代品是否会抑制吸烟引起的尼古丁摄入（Benowitz 和 Jacob 1990）。由此得出的结论是，即使受试者无法完全戒烟，尼古丁替代药物（例如透皮贴剂（当时正在进行上市前临床试验））也能抑制吸烟。我们使用氘标记的可卡因给药来研究可卡因及其代谢物苯甲酰爱康宁分布到人类头发中的时间过程。出于伦理原因，这些研究必须在可卡因滥用者中进行，并且使用标签药物可以保证随后的街头可卡因使用不会使结果无效（Henderson 等，1996）。我们还使用标记的尼古丁来研究尼古丁在头发和指甲中积累的时间过程，这似乎是尼古丁暴露的良好长期生物标志物。 此类研究需要配备合成和分析化学家以及现代分析仪器的实验室。 使用稳定同位素时，需要广泛使用质谱分析法。适当标记的药物或代谢物可能无法在商业上获得，并且需要我们在合成有机化学方面的能力来制备稳定同位素标记的药物、代谢物以及用于临床研究和测定的内标。在此申请中，我们请求为实验室和管理人员以及仪器提供支持，以维持和增强我们的分析化学能力。 行政核心要素 一个适度的行政核心设施是维持一个重要且具有成本效益的要素。 协调的临床研究支持计划。事实证明，单一办公室的统一影响力是有价值的，它可以回答或有效地重定向程序问题，帮助准备和分发文件和论文，促进专业设备和用品的购买，管理受控药物的订购，就人体受试者保护监管和程序问题提供建议，协助进度报告并为期刊手稿准备提供指导，并充当与加州大学旧金山分校会计、采购和研究管理官僚机构的接口。 其中大部分职能将作为行政核心的一部分继续存在。然而，自我们上次提交竞争性更新申请以来，加州大学旧金山分校研究人员的资源发生了重大积极变化，特别是临床与转化科学研究所 (CTSI) 的建立，这使得对行政核心的优先事项和某些职能进行一些重大重新排序是明智的。 加州大学旧金山分校是首批加入美国国立卫生研究院国家临床与转化科学联盟的学术机构之一。 UCSF CTSI 的联盟目标是转变和加强临床和转化研究，以确保尽快为患者提供最佳的健康解决方案。在 UCSF，CTSI 是一个跨校园的机构。作为国立卫生研究院 CTSA 网络的一部分，UCSF 的 CTSI 为 UCSF 研究社区提供支持临床和转化研究所需的所有主要领域的活动和基础设施，包括例如拥有 9 个不同地点的临床研究中心（正式称为 GCRC）、生物统计学、研究设计以及伦理和数据管理咨询服务，以及健康政策和社区参与计划。我们参与项目的许多成员（例如 Guydish、McCance-Katz）通过直接研究、委员会成员、参加研讨会和课程和/或作为顾问参与了 CTSI 整合。 CTSI 和相关的 UCSF 校园资源为临床研究人员提供生物统计咨询、数据管理和分析资源，比 P30 中心所提供的更加复杂和完整。研究设计的培训和咨询也是如此，例如，目前向加州大学旧金山分校所有教员和学员提供的课程包括生物统计学、临床试验、信息学和数据库管理、决策/成本分析、将实践转化为证据和定性研究方法。 可以就研究人员感兴趣的这些问题和其他问题进行咨询。 那么，有了这样的校园资源，P30 管理核心还能提供哪些额外资源呢？ 通过 CTSI 和 UCSF 生物统计部门进行的咨询提供了有用的资源。然而，作为 P30 核心支持的一部分，顾问（Delucchi 博士，也是 CTSI/生物统计部门的成员）将提供额外的适度、相对快速但更有针对性的生物统计咨询或初步咨询，该顾问在处理药物依赖性研究中最常见的数据类型和研究设计问题方面经验丰富。这将为参与项目的研究人员提供更有效、更有针对性的数据分析和数据库管理建议。这将补充生物统计司校园生物统计咨询和成果研究资源，这些资源提供优质的服务，但有时需要寻找合适的顾问并花费相当的努力让他们加快速度 一些具体的研究问题。

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.