Early Human Screening for Medication Efficacy

这份提案是P50项目申请中的项目4，该项目适用于#年拟建的跨学科研究中心 尼古丁成瘾(CIRNA)。强有力的戒烟新药的开发受阻于 部分原因是在最初对它们进行人体有效性筛选时效率低下。在我们先前工作的基础上，这 该提案旨在提高筛选药物疗效的程序的敏感性。在 实际限度，这种筛查应该模拟临床试验方法，包括使用戒烟作为 药物反应的主要指标，这可能需要有动力的研究参与者 弃权，至少是暂时的。在先前的研究中，我们发现药物(NRT贴片)比 在寻求治疗的人中使用一周，这些人内在戒烟动机较高，但外在戒烟动机较强 通过加强禁欲并没有起到任何作用。虽然信息丰富，但我们的发现是初步的，直到 它们可以与其他戒烟药物交叉验证，这是当前项目的重点。学习 1将在200名吸烟者中检查这些结果是否推广到另一种有效药物varenicline， 采用相同的混合、交叉设计，治疗寻求状态和戒断强化为 2x2受试者之间的因素，以及作为受试者内因素的varenicline与安慰剂。我们预测 在寻求治疗的人中，varenicline(与安慰剂相比)将在一周内增加戒断(即，显示疗效) 比非治疗寻求者更多，证实了内在戒烟动机对筛选的重要性。 研究2将确定在这种筛查中使用治疗寻求者是否既敏感又具体。 如果我们的程序与另一种已知的有助于戒烟的药物显示有效，将表明敏感性。 在临床试验中，安非他酮(即阳性对照)，而如果我们的程序显示 在临床试验中，已知对戒断无效的药物没有疗效，在这种情况下是莫达非尼(即， 阴性对照)。治疗寻求者(n=100)将在受试者内接受每种药物和安慰剂。 交叉设计。我们预测，与安慰剂相比，安非他酮将增加禁欲。的功效 莫达非尼，这是意想不到的，会质疑我们的程序的特异性。其次，这两项研究都将 研究个体差异和药物对早期戒断症状(渴求、戒断、 消极和积极的情感，吸烟奖励)，以确定可能的疗效机制。结果将 为改进新型戒烟药物的筛选提供直接指导，该项目的长期目标 目标和目标具有很高的公共卫生意义。

This proposal is Project 4 of a P50 application for the proposed Center for Interdisciplinary Research in Nicotine Addiction (CIRNA). Development of robust new medications for smoking cessation is hampered in part by inefficiency in how they are initially screened for efficacy in humans. Building on our prior work, this proposal is aimed at improving the sensitivity of procedures for screening medication efficacy. Within practical limits, such screening should simulate clinical trial methods, including use of smoking abstinence as the primary index of medication response, which may require study participants who are motivated to abstain, at least briefly. In prior research, we found that medication (NRT patch) increased abstinence over one week of use in treatment seekers, those with high intrinsic quit motivation, but extrinsic quit motivation via reinforcement for abstinence made no difference. Although informative, our findings are preliminary until they can be cross-validated with other cessation medications, which is the focus of the current project. Study 1 will examine in 200 smokers whether these results generalize to another effective medication, varenicline, by using the same mixed, cross-over design, with treatment seeking status and abstinence reinforcement as 2x2 between-subjects factors, and varenicline vs placebo as a within-subject factor. We predict that varenicline (vs placebo) will increase abstinence (i.e., show efficacy) over one week in treatment seekers more than in non-treatment seekers, confirming the importance of intrinsic quit motivation for screening. Study 2 will determine whether use of treatment seekers in such screening is both sensitive and specific. Sensitivity will be indicated if our procedure shows efficacy with another medication known to aid cessation in clinical trials, bupropion (i.e., a positive control), while specificity will be indicated if our procedure shows no efficacy in a medication known not to be effective for cessation in clinical trials, in this case modafinil (i.e., a negative control). Treatment seekers (n=100) will receive each medication and placebo in a within-subject cross-over design. We predict that, compared with placebo, bupropion will increase abstinence. Efficacy of modafinil, which is not expected, would question our procedure's specificity. Secondarily, both studies will examine individual differences and medication effects on symptoms of early abstinence (craving, withdrawal, negative and positive affect, smoking reward) to determine possible mechanisms of efficacy. Results will provide immediate directions for improving the screening of novel cessation medications, the project's longrange objective and a goal with very high public health significance.