A novel drug delivery system for the prevention and rescue of fentanyl and other opioid overdoses

用于预防和救援芬太尼和其他阿片类药物过量的新型药物输送系统

• 批准号: 10636330
• 负责人: Mamoun M Alhamadsheh
• 金额: $ 33.75万
• 依托单位: UNIVERSITY OF THE PACIFIC-STOCKTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10636330
• 关键词: Adderall; Adverse effects; American; Antidotes; Binding; Brain; Buprenorphine; Cessation of life; Cocaine; Dangerousness; Development; Dose; Drug Delivery Systems; Drug Kinetics; Ensure; Esters; Evaluation; FDA approved; Fentanyl; Funding; Generations; Goals; Happiness; Hepatocyte; Heroin; Human Resources; Hybrids; Hydrolysis; Illicit Drugs; In Vitro; Ingestion; Law Enforcement; Life; Ligands; Metabolic; Methamphetamine; Military Personnel; Monitor; Morphine; Naloxone; Opioid; Opioid Antagonist; Overdose; Patient-Focused Outcomes; Patients; Percocet; Persons; Pharmaceutical Preparations; Phase; Prealbumin; Precipitation; Prevention; Prodrugs; Public Health; Rattus; Renal clearance function; Reporting; Respiration; Risk; Safety; School-Age Population; Series; Serum; Serum Proteins; Subcutaneous Tissue; System; Testing; Time; Toxic effect; United States; Ventilatory Depression; Whole Body Plethysmography; Withdrawal Symptom; Xanax; absorption; antagonist; blood-brain barrier crossing; blood-brain barrier penetration; carfentanil; design; efficacy evaluation; efficacy testing; fentanyl analog; fentanyl overdose; first responder; high school; hydrophilicity; in vivo; mass casualty; milligram; mu opioid receptors; nalmefene; novel therapeutics; opioid epidemic; opioid mortality; opioid overdose; opioid use disorder; opioid withdrawal; overdose death; pill; prevent; side effect; subcutaneous; synthetic opioid; weapons

Opioids have significant adverse effects highlighted by the large number of patients with opioid use disorder (OUD) and the increasing number of overdose deaths in the United States and elsewhere. In just the 12-month period ending in November 2021, more than 107,000 Americans died from drug overdose. Around 66% of these deaths involved illicit synthetic opioids like fentanyl (approximately 50 times more potent than heroin and 100 times more potent than morphine), which is the primary driver of the opioid epidemic today. Many of the opioid overdose deaths are attributed to fentanyl mixed with other illicit drugs like heroin, cocaine, and methamphetamine. The potential lethal dose of fentanyl is around two milligrams, and it is particularly dangerous for opioid naïve people who do not have a tolerance to opioids. Overdose deaths among high school-aged Americans have more than doubled since 2019, which has been attributed to counterfeit pills (e.g., Xanax, Percocet, Adderall) laced with a lethal amount of fentanyl. Sadly, many users often ingest the deadly drug unknowingly. Unfortunately, there is not a happy ending for this devastating story and there is no easy solution to the synthetic opioid problem. The vulnerability of our nation to the weaponization of highly potent fentanyl analogs, such as carfentanil (20-fold more potent than fentanyl), poses a significant public health risk not only to civilians, but also to first responders, law enforcement personnel, and the military. The relatively short duration of action (DOA) of the mu-opioid receptor antagonists, naloxone and nalmefene, poses a major challenge for its efficacy against fentanyl overdose. It is difficult to imagine how naloxone and nalmefene could be deployed effectively in a mass casualty situation involving synthetic opioids (where duration of overdose could last up to 24 hr). The overall goal of this proposal is to develop a fundamentally novel drug delivery approach for extending the DOA of currently FDA-approved opioid overdose antidotes (naloxone and nalmefene) for 24 hr or more. Here we report the development of a new generation of opioid antagonist prodrugs as a countermeasure for synthetic opioid overdose. The main advantages of our system include the following: (i) use of two FDA-approved antidotes, naloxone and nalmefene, with well-established safety and efficacy profiles; (ii) potential to reverse AND effectively protect against re-narcotization by synthetic opioid overdose; (iii) potential to avoid the precipitation of opioid withdrawal symptoms; and (iv) ability to administer the prodrugs subcutaneously. The main hypothesis of this proposal is to test whether conjugation of FDA-approved opioid antagonists through a cleavable ester linker to a selective ligand for the serum protein, transthyretin (TTR), would allow us to generate opioid antagonist prodrugs that are hydrophilic and can bind reversibly to TTR in serum. The balanced hydrophilicity of prodrug will be important for achieving rapid absorption of the prodrug from the subcutaneous tissue while binding to TTR would extend the DOA of the prodrugs.

阿片类药物具有严重的不良反应，大量的阿片类药物USorders （OUD）在美国和Elsewere中越来越多的过量死亡。 截至2021年11月的时期，有107,000多名美国人死于药物过量。 死亡涉及非法合成阿片类药物，例如芬太尼（比海洛因更有效，100 100 时代比吗啡更强大，这是当今阿片类药物流行的主要驱动力。 过量死亡归因于芬太尼与其他其他LICIT药物混合，例如海洛因，可卡因和 甲基苯丙胺的潜在致命剂量约为两毫克，这特别危险 对于不容忍阿片类药物的阿片类药物。 自2019年以来，美国人的两倍多，这归因于假药（例如xanax，， percocet，adderall）可悲的是，许多用户经常摄取致命的毒品。 不幸的是。 综合阿片类药物问题。 类似物，例如carfentanil（比芬太尼高20倍），不仅构成了公共卫生风险的重大风险。 平民，以及第一兵，执法人员和军队。 Mu-Apioid受体拮抗剂Naloxone和Nalmefene的作用（DOA）为其构造 对芬太尼过量的功效。 在大规模伤亡情况下有效合成阿片类药物 24小时）。 当前由FDA批准的阿片类药物过量解毒剂（纳洛酮和纳米芬）的DOA持续24小时或更高。 我们报告了新一代阿片类拮抗剂前药的发展，以作为合成的对策 阿片类药物过量。 解毒剂，纳洛酮和纳米酮，具有良好的安全性和功效; 并有效防止合成阿片类药物过量的重新纳入； 阿片类药物戒断症状的降水； 该提案的假设是测试是在FDA批准的阿片类药物拮抗剂时测试的 可切合的酯连接器到血清蛋白的选择性配体transthyretin（ttr），我会生成 阿片类拮抗剂前药是亲水性的，并结合血清中的TTR 前药的亲水性对于从皮下快速吸收前药很重要 与TTR结合的组织会扩展前药的DOA OFA。