Reversal of ventilatory depression by drug mixtures

摘要 在12个月内(2020年4月至4月)，首次有超过10万人死于药物过量 2021年)在美国。合成阿片类药物，主要是芬太尼，占所有过量死亡的60%以上 在此期间(87%的阿片类药物过量死亡)。在过去的十年里，服药过量死亡的人数 涉及合成阿片类药物的人数增加了20倍，2020年接近6万人。芬太尼类似物的出现， 其中一些比芬太尼有效得多(例如卡芬太尼，据报道比芬太尼强100倍 芬太尼)，对公众健康构成严重威胁。接触这些药物的另一个危险特征是 它们主要是在不知情的情况下服用的，再加上它们的效力，增加了过量服药的风险。 阿片受体拮抗剂纳洛酮是FDA批准的唯一治疗阿片类药物过量的药物。而当 纳洛酮已经拯救了无数人的生命，其有效性受到其作用时间短的限制，而且其 对抗是竞争性的，即纳洛酮的影响可以通过服用更多的阿片类药物来克服。 激动剂。临床报告表明，需要更大或更频繁的纳洛酮来逆转阿片类药物。 过量涉及卡芬太尼或其他芬太尼类似物，以及临床前研究表明 阿片类拮抗剂对抗卡芬太尼相对于其他阿片激动剂的作用。新型阿片类药物 受体拮抗剂美索那莫司(MCAM)非竞争性地结合在Mu阿片受体上，并具有 非常持久的影响。最近的一项研究表明，MCAM的一些作用是通过 与u阿片受体上的变构结合。这一发现值得进一步研究，并为 评估使用拮抗剂混合物逆转阿片类药物诱导的呼吸机能抑制的可能性。这个 拟议的研究使用大鼠全身体积描记术来解决阿片类药物过量死亡的当前趋势 以及开发新的阿片类药物过量治疗方案的必要性，验证了以下假设 阿片类激动剂的混合物在单独给药时的效果比每种药物都大，而且 阿片类拮抗剂纳洛酮和MCAM在逆转阿片类药物作用方面将比单独使用纳洛酮更有效 呼吸机上的激动剂。目标1将确定海洛因、芬太尼、 和卡芬太尼的通气量。目标2将确定纳洛酮、MCAM和MCAM之间相互作用的性质 异丙诺啡可逆转海洛因、芬太尼和卡芬太尼的呼吸机抑制作用，并开始 评估这种相互作用的机制。拟议的研究将确定相互作用的性质 阿片类激动剂通常涉及阿片类药物过量，并评估阿片类拮抗剂的混合物是否可能 是逆转阿片类药物过量的更有效的纳洛酮替代品。这些研究的结果将提供 与阿片类药物过量死亡的最新趋势和可能的改善有关的宝贵信息 阿片类药物过量治疗。拟议的培训计划将发展我的设计、指挥和 传播我的独立研究，为成为一名成功的独立调查员铺平道路。

ABSTRACT For the first time, over 100,000 deaths were caused by drug overdose in a 12-month period (April 2020 - April 2021) in the United States. Synthetic opioids, primarily fentanyl, accounted for over 60% of all overdose deaths during this span (87% of opioid overdose deaths). Over the past decade, the number of overdose deaths involving synthetic opioids has risen 20-fold, approaching 60,000 in 2020. The emergence of fentanyl analogs, some of which are much more potent than fentanyl (e.g., carfentanil, reported to be ~100 times more potent than fentanyl), pose serious risk to public health. Another dangerous characteristic of exposure to these drugs is that they are predominantly taken unknowingly which, combined with their potency, increases the risk of overdose. The opioid receptor antagonist naloxone is the only FDA-approved treatment for opioid overdose. While naloxone has saved countless lives, its effectiveness is limited by its short duration of action and that its antagonism is competitive – that is, that the effects of naloxone can be surmounted by taking more of an opioid agonist. Clinical reports suggest that larger or more frequent doses of naloxone are required to reverse opioid overdose involving carfentanil or other fentanyl analogs, and preclinical studies show reduced effectiveness of opioid antagonists to antagonize the effects of carfentanil relative to other opioid agonists. The novel opioid receptor antagonist methocinnamox (MCAM) binds non-competitively at the mu opioid receptor and has extremely long-lasting effects. A recent study demonstrated that some effects of MCAM are mediated through binding an allosteric site on the mu opioid receptor. This finding warrants further study and provides rationale for evaluating the potential of using mixtures of antagonists to reverse opioid-induced ventilatory depression. The proposed studies use whole-body plethysmography in rats to address current trends in opioid overdose death and the need for development of new treatment options for opioid overdose, testing the hypotheses that the effects of mixtures of opioid agonists will be greater than each drug when given alone, and that mixtures of the opioid antagonists naloxone and MCAM will be more potent than naloxone alone at reversing the effects of opioid agonists on ventilation. Aim 1 will determine the nature of the interaction between the effects of heroin, fentanyl, and carfentanil on ventilation. Aim 2 will determine the nature of the interactions between naloxone, MCAM, and diprenorphine for reversing the ventilatory depressive effects of heroin, fentanyl, and carfentanil, and begin to assess the mechanism of this interaction. The proposed studies will determine the nature of interactions between opioid agonists commonly involved in opioid overdose and evaluate whether mixtures of opioid antagonists might be more effective alternatives to naloxone for reversing opioid overdose. Results from these studies will provide valuable information related to recent trends in opioid overdose death and possible improvements in the treatment of opioid overdose. The proposed training plan will develop my skills at designing, conducting, and disseminating my independent research, paving the way to becoming a successful independent investigator.