芬太尼和芬太尼类似物(F/FA)由于其易于合成和极高的效力,已成为在伪造处方药和非法街头药物混合物中越来越常见的掺假物。由F/FA引发的致命过量的持续流行继续强调需要比纳洛酮(NLX)更长效的疗法,目前扭转阿片类药物过量的黄金标准,这表明预防与F/FA毒性相关的复性的功效有限。一种基于共价纳洛酮纳米颗粒(cNLX-NP)的新型阿片类药物逆转剂已被证明可以使芬太尼诱导的呼吸抑制达到48小时,证明其潜在的治疗效用。这项研究的目的是表征cNLX-NP逆转芬太尼诱导的呼吸效应的速度及其保护作用的持续时间。
■SpragueDawley雄性大鼠(n=6/组)在血氧计上测试了用0.1mg/kgSC芬太尼攻击的基线动脉血氧饱和度百分比(%SaO2),并在15分钟后给予10mg/kgIM剂量的NLX,纳美芬(NLMF),或cNLX-NP,并通过血氧饱和度连续监测10分钟。一周后,在先前单独接受NLX的大鼠中使用NLX:cNLX-NP的1:1混合物作为逆转剂重复实验。
■虽然NLX和NLMF在1分钟内迅速将%SaO2逆转至基线,接受cNLX-NP的大鼠直到给药后9分钟才恢复到>90%SaO2水平。同样,在使用NLX和NLMF治疗后1分钟内,心率和呼吸频率恢复至基线水平,但直到cNLX-NP给药后10分钟才恢复至基线水平.相比之下,NLX:cNLX-NP在一分钟内逆转了所有芬太尼诱导的呼吸抑制作用。
■虽然单独使用cNLX-NP不能及时充分逆转F/FA过量,将游离NLX与cNLX-NP混合可提供一种机制,既可快速逆转芬太尼相关效应,又可维持对合成阿片类药物毒性的长期保护作用.这些数据支持cNLX-NP作为一种快速和持久的解毒剂的进一步发展,以治疗F/FA引起的呼吸抑制和过量。并有可能防止人类的再肉瘤化。
UNASSIGNED: Fentanyl and fentanyl analogs (F/FA) have become increasingly common adulterants in counterfeit prescription pills and illicit street drug mixtures due to their ease of synthesis and exceedingly high potency. The ongoing epidemic of fatal overdoses fueled by F/FA continues to highlight the need for longer-acting therapies than naloxone (NLX), the current gold-standard for reversing opioid overdoses, which shows limited efficacy to prevent renarcotization associated with F/FA toxicity. A novel opioid reversal agent based on covalent naloxone nanoparticles (cNLX-NP) has been shown to blunt fentanyl-induced respiratory depression out to 48 hr, demonstrating its potential therapeutic utility. The purpose of this study was to characterize how rapidly cNLX-NP reverses fentanyl-induced respiratory effects as well as the duration of its protective effects.
UNASSIGNED: Sprague Dawley male rats (n=6/group) were tested on an oximeter for baseline percent arterial oxygen saturation (%SaO2) challenged with 0.1 mg/kg SC fentanyl and 15 min later given 10 mg/kg IM doses of NLX, nalmefene (NLMF), or cNLX-NP and continuously monitored via oximetry for 10 minutes. One week later the experiment was repeated using a 1:1 mixture of NLX:cNLX-NP as the reversal agent in the rats that previously received NLX alone.
UNASSIGNED: While both NLX and NLMF rapidly reversed %SaO2 to baseline within 1 min, rats that received cNLX-NP did not return to >90% SaO2 levels until 9 min after administration. Similarly, heart and breath rates returned to baseline within 1 min of treatment with NLX and NLMF but did not return to baseline until 10 minutes after cNLX-NP administration. In contrast, NLX:cNLX-NP reversed all fentanyl-induced respiratory depressive effects within one minute.
UNASSIGNED: While cNLX-NP alone may not sufficiently reverse F/FA overdose in a timely manner, mixing free NLX with cNLX-NP can provide a mechanism to both rapidly reverse fentanyl-related effects and maintain extended protection against synthetic opioid toxicity. These data support further development of cNLX-NP as a fast-acting and long-lasting antidote to treat F/FA-induced respiratory depression and overdose, and potentially prevent renarcotization in humans.