SCIENTIFIC, TECHNICAL AND OTHER PROFESSIONAL SUPPORT SERVICES (STOPS)

科学、技术和其他专业支持服务（停止）

基本信息

批准号：
10291118
负责人：
SARA SPROSE
金额：
$ 16.12万
依托单位：
KELLY SERVICES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-14 至 2021-07-13
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10291118
关键词：
Abstinence Accounting Acquired Immunodeficiency Syndrome Acute Adverse event Affinity African American Age Alcohols Amygdaloid structure Animal Model Animals Anterior Anti-Anxiety Agents Anti-Inflammatory Agents Anti-Retroviral Agents Anus Area Area Under Curve Arrhythmia Baltimore Behavior Binding Biological Biological Assay Biological Markers Biological Models Body mass index Bolus Infusion Brain Brain imaging Breast C-reactive protein CCL3 gene CD14 gene CD4 Positive T Lymphocytes CXCL10 gene CXCL11 gene CXCL9 gene CYP3A4 gene Cannabis Carbohydrates Carbon Monoxide Cardiac Cardiovascular system Categories Cell Count Characteristics Chi-Square Tests Chinese Traditional Medicine Chronic Chronic Obstructive Airway Disease Cigarette Clinic Clinical Clinical Research Clinical Trials Cohort Effect Collaborations Communicable Diseases Confidence Intervals Control Animal Controlled Clinical Trials Corpus striatum structure Cotinine Cues Custom Cytochrome P450 DSM-V Data Dependence Detection Development Development Plans Diabetes Mellitus Diagnosis District of Columbia Dopamine Dopamine Receptor Dose Double-Blind Method Drug Interactions Drug Kinetics Drug usage Enrollment Ensure Enzyme-Linked Immunosorbent Assay Enzymes Ethnic Origin Event Exhalation FDA approved Fatty Acids Fatty acid glycerol esters Feedback Food Funding General Population Guidelines HIV HIV Infections Half-Life Head and neck structure Hepatitis B Hepatitis C Heroin Homeostasis Hour Human IL8 gene Image Analysis Immunologic Markers Immunomodulators In Vitro Incidence Individual Infection Inflammatory Response Infusion procedures Injections Institutes Instruction Insula of Reil Intention Interferon Type II Interleukin-18 Interleukin-2 Interleukin-6 Intervention Investigation Kidney Diseases Kudzu Laboratories Laboratory Markers Link Lipids Low income Lung Malignant Neoplasms Manufacturer Name Maryland Measurement Measures Mediating Metabolic Methamphetamine Midazolam Minnesota Modality Modeling Modification Morbidity - disease rate Morphine Neurons Neurosciences Nicotine Nicotine Dependence Nucleus Accumbens Oral Oral Administration Outcome Pamphlets Participant Patients Pattern Performance Peripheral Pharmaceutical Preparations Pharmacology Phase Phase III Clinical Trials Placebo Control Placebos Plant Roots Population Positron-Emission Tomography Prevalence Probability Procedures Property Prospective cohort Prostate Protocols documentation Psychiatry Questionnaires RNA Race Raclopride Randomized Rank-Sum Tests Rattus Recording of previous events Recovery Regimen Relapse Research Research Personnel Risk Rodent Model Safety Sample Size Sampling Screening procedure Self Administration Seminal Serum Services Severities Signal Transduction Skin Smoker Smoking Smoking History Smoking Status Specific qualifier value Substance Addiction Substance Use Disorder Substance abuse problem System TNF gene Technology Testing Therapeutic Therapeutic Effect Time Tobacco Tobacco Use Disorder Tobacco smoking behavior Tobacco use Troponin Troponin I Troponin T Tyrosine 3-Monooxygenase UGT1A1 enzyme United States United States National Institutes of Health Universities Urine Ventral Tegmental Area Withdrawal Symptom Woman addiction aged aldehyde dehydrogenases base cardiovascular disorder risk chemokine clinical center clinically relevant clinically significant cohort comorbidity control trial craving cytokine daidzin dosage drinking drug seeking behavior effective intervention effective therapy evidence base first-in-human frontal lobe group intervention healthy volunteer human study inflammatory marker inhibitor/antagonist interest men mortality neurochemistry nicotine use non-smoker non-smoking novel strategies novel therapeutics opioid use disorder patient population phase I trial placebo group pre-clinical preclinical study preclinical trial predicting response prevent primary endpoint psychologic radiotracer recruit relapse prediction research and development research clinical testing response sample collection screening sex small molecule smoking cessation smoking cue stem systematic review treatment duration treatment group treatment strategy varenicline willingness

项目摘要

Significance and Background For the general population of the United States, tobacco use disorder (TUD) is well-recognized to be the leading preventable cause of death1,2. What is not as well appreciated is that in people with HIV (PWH), the prevalence of tobacco use is three times higher compared to the general population, and there is corresponding enhanced morbidity and mortality: TUD has substantial consequences in PWH3,4. While there is appropriate emphasis on sophisticated approaches to enhancing the quality and duration of survival for PWH by using more potent antiretrovirals, immunomodulators, and anti-inflammatory agents, effective treatment of TUD in this population would likely have at least comparable benefit to any of these strategies. More effective use of currently available therapeutic modalities for TUD should be implemented more widely, however, the poor performance of any current approach suggests that new and more effective interventions are needed. A systematic review conducted by our group shows the rates of CVD have tripled in PWH in the last 2 decades, conferring a 2-fold risk for CVD compared to the general population5, and TUD magnifies this risk6,7. Despite the disproportionate morbidity and mortality, PWH are less likely to quit smoking compared to the general population7-9. There is a scarcity of research on effective smoking cessation strategies for PWH10,11, since these individuals were excluded from studies evaluating the efficacy of pharmacologic smoking cessation strategies7,12. One of the few randomized control trials available on PWH and smoking cessation13 demonstrated that the use of varenicline was safe and had a higher rate of smoking cessation in PWH compared to placebo, however, the continued abstinence rate of 18% was significantly lower than the rate of up to 70% in phase III clinical trials of varenicline(which enrolled non-HIV infected individuals)14. The lack of evidence-based, effective smoking cessation strategies and the low smoking cessation rates among PWH highlight the need for novel therapeutic strategies for TUD in order to reduce tobacco-related morbidity and mortality in all populations, including PWH. TUD in DC is disproportionately high compared to other areas in the U.S. According to DC Cohort data (a prospective cohort that is a part of DC PFAP, N=7160), 42.3% are current smokers15, compared to an estimated prevalence of 17.1% in the United States16,17. In 2016, of 6,329 DC cohort participants, 230 (3.6%) had an incident diagnosis of COPD. In addition, the incidence of non-AIDS defining cancers was higher than AIDS-defining cancers in the DC Cohort between 2011 and 201718. The most common cancers were breast, prostate, skin, anal, head/neck, and lung cancer18, all of which are associated with tobacco use19-28. More than 65% of current smokers in the U.S. want to quit smoking29, however, over 50% of those who attempt to quit relapse and begin smoking again within a year30. Predictors of relapse include craving31; during chronic use, craving is mediated by the persistent release of dopamine and recruitment of the amygdala, anterior cingulate, orbitofrontal cortex, and dorsolateral prefrontal cortex32. Though this dopamine surge is a central part of addictions, including addiction to nicotine33, the mechanisms of the available FDA- approved pharmacologic therapies do not address the dopamine surge and subsequent craving that is associated with addiction and relapse, thus predisposing to failed quit attempts. Therefore, modulating the CNS dopamine response in order to reduce tobacco craving is an unexplored but important strategy to treat TUD. This proposal aims to assess a novel approach to managing craving for tobacco using ANS-6637, a first-in-class aldehyde dehydrogenase 2 (ALDH-2) inhibitor, which prevents dopamine surge, inhibits craving, and decreases nicotine use in animal models. While this drug is currently in early stage development for opioid use disorder and potentially for alcohol, it is important to recognize that all substance use disorders may not respond identically to one pharmacologic intervention and all patient groups are not identical (e.g. PWH and non-HIV infected), therefore, separate investigations are warranted. It might be thought that this was an obvious target for intramural funding but assiduous efforts with all logical institutes have indicated lack of interest in TUD and HIV, although OAR considers such morbidities to be a priority. We are in close contact with Amygdala Neurosciences in terms of its development plans, and we have a ready population of patients, good data about TUD in Maryland and the District of Columbia, strong links to translational issues with biologic correlates, close ties to the appropriate populations of patients in existing clinics which this group staffs, and a track record of rapid protocol implementation and completion. Our clinics in Baltimore and DC serve low-income African American patients almost exclusively, and this population in particular could derive benefit from a successful treatment strategy, given its rates of TUD and CVD. This study is a collaboration between NIH-CC CCMD, NIH CC PET, University of Maryland Infectious Diseases, District of Columbia Partnership for AIDS Progress, and the University of Maryland Department of Psychiatry.

意义和背景对于美国的一般人群，烟草使用障碍（TUD）被广泛认可是可预防的死亡原因1,2。不太理解的是，在艾滋病毒（PWH）患者中，烟草使用率与普通人群相比高三倍，并且发病率和死亡率相应：TUD在PWH3,4中产生了实质性后果。尽管通过使用更有效的抗逆转录病毒，免疫调节剂和抗炎药来提高PWH的生存质量和生存期的精致方法，但在该人群中对TUD的有效治疗可能至少与任何这些策略相当。应更广泛地实施当前可用的治疗方式的TUD，但是，任何当前方法的性能差表明需要新的，更有效的干预措施。我们小组进行的系统审查表明，在过去的20年中，PWH的CVD发生率增加了两倍，与一般人群相比，CVD的风险为2倍，TUD扩大了这一风险6,7。尽管发病率和死亡率不成比例，但与一般人群相比，PWH戒烟的可能性较小。关于PWH10,11的有效戒烟策略的研究稀缺，因为这些人被排除在评估药物吸烟戒烟策略的疗效的研究之外。7,12。与安慰剂相比，在PWH和戒烟上可用的为数不多的随机对照试验之一表明，在PWH中使用varenicline是安全的，并且在PWH中使用戒烟的速度更高，但是，持续的戒烟率为18％的持续戒烟率显着降低了远低于在III阶段III临床试验中的持续戒烟率（该持续性非-HIV）（该临床中的非-HIV次数）14。 PWH中缺乏基于证据的，有效的戒烟策略和低吸烟率，强调了对TUD的新型治疗策略的需求，以便在包括PWH在内的所有人群中降低与烟草相关的发病率和死亡率。根据DC队列数据（这是DC PFAP的一部分，N = 7160的一部分），DC中的TUD与美国其他地区相比，与美国其他地区相比，目前的吸烟者为42.3％，而美国的估计患病率为17.1％。 2016年，有6,329名DC队列参与者有230名（3.6％）的COPD诊断。此外，在2011年至2017年之间，定义癌症的非AID癌的发生率高于DC队列中定义的癌症。最常见的癌症是乳腺癌，前列腺，皮肤，肛门，头颈和肺癌18，所有这些癌症都与Tobacco Use19-28相关。在美国，超过65％的吸烟者希望戒烟29，但是，超过50％的人试图退出复发并在一年之内再次吸烟。复发的预测因素包括渴望31；在长期使用过程中，渴望是通过多巴胺的持续释放和杏仁核，前扣带回，眶额皮层和背侧前额叶皮层的募集来介导的。尽管这种多巴胺激增是成瘾的核心部分，包括对尼古丁33的成瘾，但可用的FDA-批准的药理学疗法的机制并不能解决多巴胺激增和随后渴望与成瘾和复发有关的渴望，从而易于退出尝试。因此，调节中枢神经系统多巴胺反应以减少烟草的渴望是治疗TUD的一个未开发但重要的策略。该提案旨在评估一种新的方法，用于使用ANS-6637（一种一流的醛醛脱氢酶2（ALDH-2）抑制剂来管理烟草的渴望，可防止多巴胺激增，抑制渴望，并降低动物模型中的氨基氨酸乳腺素。尽管该药物目前正处于阿片类药物使用障碍的早期开发中，并且潜在的酒精疾病可能认识到，所有药物使用障碍可能不会对一种药理干预措施做出相同的反应，并且所有患者组并不相同（例如，PWH和非HIV感染），因此，必须进行单独的研究。可能认为这是壁内资金的一个明显目标，但是与所有逻辑机构的艰苦努力表明对TUD和HIV缺乏兴趣，尽管OAR认为这种病态是当务之急。就其开发计划而言，我们与杏仁核神经科学有着密切的联系，并且我们有很多患者人群，有关Maryland和哥伦比亚特区TUD的良好数据，与生物学相关性的转化问题的密切联系，与现有诊所的适当患者人群紧密联系，该组员工的适当患者人群以及快速的协议实施和完成协议。我们在巴尔的摩和DC的诊所几乎完全服务于低收入非裔美国人患者，鉴于其TUD和CVD率，该人群可能会从成功的治疗策略中获得收益。这项研究是NIH-CC CCMD，NIH CC PET，马里兰州大学传染病，哥伦比亚特区艾滋病进步伙伴关系的合作，马里兰大学精神病学系。