A Breath-based Naltrexone Adherence Tool to Manage Narcotic-addicted HIV patients

基于呼吸的纳曲酮依从性工具用于管理麻醉成瘾的艾滋病毒患者

• 批准号: 8263470
• 负责人: DONN MICHAEL DENNIS
• 金额: $ 16.32万
• 依托单位: XHALE, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8263470
• 关键词: 2-butanol; AIDS/HIV problem; Accounting; Acquired Immunodeficiency Syndrome; Adherence; Alcohol dehydrogenase; Alcohols; Americas; Behavior Therapy; Behavioral; Biometry; Blood; Clinical Sciences; Communication; Complex; Cross-Over Studies; Deception; Detection; Development; Direct Costs; Directly Observed Therapy; Double-Blind Method; Drug Formulations; Ethanol; Exhalation; Facilities and Administrative Costs; Florida; Food; Future; Gas Chromatography; Generations; Genetic Polymorphism; Goals; HIV; HIV Infections; Health Insurance Portability and Accountability Act; Home environment; Human; In Vitro; Incidence; Individual; Ingestion; Institutes; Intravenous Drug Abuse; Ketones; Kinetics; Legal patent; Link; Mass Spectrum Analysis; Measures; Medicine; Micelles; Modeling; Monitor; Naltrexone; Narcotic Addiction; Narcotics; National Institute of Drug Abuse; Oils; Opiate Addiction; Opiates; Opioid; Oral; Oral Administration; Outpatients; Patients; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Protein Isoforms; Randomized; Regimen; Relapse; Research Design; Small Business Innovation Research Grant; Stomach; System; Technology; Testing; Therapeutic Equivalency; Time; Translational Research; Universities; Vagina; Vision; Water; Work; addiction; base; capsule; cost; design; effective therapy; healthy volunteer; medication compliance; metal oxide; methylethyl ketone; multidisciplinary; novel; prevent; programs; sensor; tool; transmission process

DESCRIPTION (provided by applicant): Addiction annually costs America >$500B. Narcotic addiction is especially worrisome since intravenous drug abuse (IVDA) also promotes HIV transmission. Reducing IVDA is critical to lowering the incidence of HIV. Since >75% of IVDA is with opioids, effective treatment of opiate addiction should markedly reduce IVDA and lower HIV transmission rates. Naltrexone has markedly lowered relapse rates and shortened treatment time in opiate-addicted patients when combined with standard behavioral therapies. This efficacy, however, is dependent upon strict adherence, and monitoring this adherence relies primarily upon directly observed therapy (DOT). The focus of this program is to develop a novel medication adherence monitoring system that can realistically monitor whether narcotic addicts actually ingest their oral naltrexone on a regular basis, completely independent of DOT. In this patented system, innocuous "taggants" (chosen from FDA "Generally Recognized as Safe" list) are "packaged" with the active pharmaceutical ingredient (e.g., naltrexone) into a "smart" drug formulation. After the drug is ingested and enters the stomach, the taggant is released and rapidly metabolized to a volatile metabolite. Detection of the volatile metabolite in the breath verifies oral ingestion of the drug. We previously established that this system, directed at accurately assessing adherence in humans, is technically feasible. Notable development findings include: 1) secondary (2o) alcohols (e.g., 2-butanol) are superior taggants metabolized by alcohol dehydrogenase (ADH is not subject to genetic polymorphisms, unlike the isoform) to generate volatile ketones (e.g., 2-butanone) exhaled in breath, 2) a miniature gas chromatography-metal oxide sensor (mGC-MOS) has been created to measure ketones in human breath, 3) multiple taggants can be readily incorporated into the system to monitor adherence for several drugs, and 4) food does not interfere with the system. We now propose to specifically adapt and expand this core technology to manage opioid-addicted patients with HIV/AIDS. To that end, the following 2 aims will be achieved: Aim 1: Create 8 SMART capsule-based naltrexone systems using 4 general types of pharma formulation strategies. Model naltrexone (50 mg) formulations containing the GRAS taggant, 2-butanol (25 or 40 mg) will be prepared and preliminary stability studies executed: Type 1) hydrophobic system, Type 2) hydrophilic system, Type 3) reverse micelle system, and Type 4) water-in-oil microemulsion system (Months 1-6). Aim 2: Select the best naltrexone formulation and test mGC-MOS performance in healthy volunteers in the UF Clinical and Translational Science Institute (CTSI). Using a double blind, randomized, crossover study design, the relationship between the breath concentration (measured via mGC-MOS and gas chromatography mass spectroscopy [GC-MS]) of 2-butanol (taggant) and 2-butanone (metabolite) versus time will be determined after the oral administration of 3 promising naltrexone formulations selected from Aim 1 or a positive control (Months 7-12). PUBLIC HEALTH RELEVANCE: The goal of this Phase I SBIR program is to develop a novel breath-based medication adherence monitoring system that can realistically monitor whether opiate addicts with HIV/AIDS actually ingest (definitive adherence) their oral naltrexone on a regular basis, completely independent of the need for directly observed therapy.

描述（由申请人提供）：成瘾每年花费美国超过5000亿美元。麻醉品成瘾尤其令人担忧，因为静脉注射吸毒也会促进艾滋病毒的传播。减少IVDA对降低艾滋病毒的发病率至关重要。由于>75%的IVDA与阿片类药物有关，因此有效的阿片类药物成瘾治疗应显着减少IVDA并降低HIV传播率。纳洛酮与标准行为疗法联合使用时，可显著降低阿片类药物成瘾患者的复发率，缩短治疗时间。然而，这种疗效取决于严格的依从性，并且监测这种依从性主要依赖于直接观察治疗（DOT）。该计划的重点是开发一种新型的药物依从性监测系统，该系统可以真实地监测麻醉成瘾者是否定期服用口服纳洛酮，完全独立于DOT。在该专利系统中，无害的“标签剂”（选自FDA“公认安全”列表）与活性药物成分（例如，纳洛酮）转化为“智能”药物制剂。在药物被摄入并进入胃后，标记物被释放并迅速代谢为挥发性代谢物。呼吸中挥发性代谢物的检测证实了药物的口服摄入。我们之前已经确定，这个系统，旨在准确评估人类的依从性，在技术上是可行的。值得注意的开发发现包括：1）仲（20）醇（例如，2-丁醇）是由醇脱氢酶代谢的上级标记物（ADH不受遗传多态性的影响，与同种型不同）以产生挥发性酮（例如，2-丁酮），2）已经创建了微型气相色谱-金属氧化物传感器（mGC-MOS）来测量人类呼吸中的酮，3）多种标记物可以容易地并入系统中以监测几种药物的依从性，以及4）食物不会干扰系统。我们现在建议专门调整和扩展这一核心技术，以管理患有艾滋病毒/艾滋病的阿片类药物成瘾患者。为此，将实现以下2个目标：目标1：使用4种一般类型的药物制剂策略创建8种基于SMART胶囊的纳洛酮系统。将制备含有GRAS标记物2-丁醇（25或40 mg）的模型纳洛酮（50 mg）制剂，并进行初步稳定性研究：1型）疏水系统，2型）亲水系统，3型）反胶束系统和4型）油包水微乳液系统（1-6个月）。 目标二：选择最好的纳洛酮配方和测试mGC-MOS性能在健康志愿者在UF临床和转化科学研究所（CTSI）。采用双盲、随机、交叉研究设计，在口服选自目标1或阳性对照的3种有前景的纳洛酮制剂后（第7-12个月），确定2-丁醇（标记物）和2-丁酮（代谢物）的呼气浓度（通过mGC-MOS和气相色谱质谱[GC-MS]测量）与时间之间的关系。 公共卫生关系：第一阶段SBIR计划的目标是开发一种新的基于呼吸的药物依从性监测系统，该系统可以真实地监测患有艾滋病毒/艾滋病的阿片类药物成瘾者是否定期服用（最终依从性）他们的口服纳洛酮，完全独立于直接观察治疗的需要。