Department of Pharmaceutical Science, Marshall University School of Pharmacy, Stephen J. Kopp Hall 353, 1 John Marshall Drive, Huntington, WV 25755, USA.
Department of Pharmaceutical Science, Marshall University School of Pharmacy, Stephen J. Kopp Hall 353, 1 John Marshall Drive, Huntington, WV 25755, USA.
Drug Alcohol Depend. 2024 Jun 1;259:111301. doi: 10.1016/j.drugalcdep.2024.111301. Epub 2024 Apr 16.
The incidence of combination methamphetamine (METH)-opioid overdose has substantially increased in recent years. While agitation is uncommon after the naloxone (NLX) reversal of opioids, it is a major clinical concern in acute METH intoxication and can be physiologically antagonized by opioid-induced sedation. This study aimed to perform initial preclinical analysis of the safety and efficacy of dexmedetomidine (DEXMED) co-administered with NLX to attenuate METH-induced locomotor activity, as a rat model of agitation, after the reversal of fentanyl (FENT)-induced sedation.
Male Sprague Dawley rats were administered subcutaneous (SC) 0.1mg/kg FENT ± 1mg/kg METH. Fifteen min later, SC 0.1mg/kg NLX ± an increasing (0, 0.032, 0.056, and 0.1mg/kg) DEXMED dose was administered prior to the measurement of locomotor activity. After a washout period, the FENT ± METH and NLX ± DEXMED administration with the highest dose of DEXMED was administered for measurement of blood oxygen saturation and heart rate.
After the NLX reversal of FENT-induced sedation, adjunct DEXMED substantially and significantly reduced METH-induced locomotor activity (p<0.05) at all doses tested. While the addition of DEXMED did not significantly reduce blood oxygenation in METH treated rats, it did so in the absence of METH. Also, DEXMED significantly reduced heart rate compared to non-DEXMED treated groups and resulted in further significant reductions in the animals not exposed to METH (p<0.05).
These data provide preclinical evidence that DEXMED may be a safe and effective chemical restraint for METH-induced agitation after NLX opioid reversal.
近年来，组合使用甲基苯丙胺（METH）和阿片类药物导致的过量用药的发生率显著增加。虽然纳洛酮（NLX）逆转阿片类药物的作用后通常不会出现激越，但在急性 METH 中毒中这是一个主要的临床关注点，且激越可以被阿片类药物引起的镇静作用所拮抗。本研究旨在对右美托咪定（DEXMED）与 NLX 联合使用以减轻 METH 诱导的运动活性进行初步的临床前分析，作为一种逆转芬太尼（FENT）诱导镇静后 METH 诱导激越的大鼠模型。
雄性 Sprague Dawley 大鼠给予皮下（SC）注射 0.1mg/kg FENT ± 1mg/kg METH。15 分钟后，在测量运动活性之前，给予 SC 注射 0.1mg/kg NLX ± 递增剂量（0、0.032、0.056 和 0.1mg/kg）的 DEXMED。在洗脱期后，给予 FENT ± METH 和 NLX ± DEXMED 联合最高剂量的 DEXMED 以测量血氧饱和度和心率。
在 NLX 逆转 FENT 诱导的镇静后，辅助 DEXMED 以所有测试剂量显著降低 METH 诱导的运动活性（p<0.05）。虽然 DEXMED 的添加并未显著降低 METH 治疗大鼠的血氧饱和度，但在无 METH 存在的情况下，DEXMED 降低了心率。DEXMED 还显著降低了与未接受 DEXMED 治疗的大鼠相比的心率，并导致未暴露于 METH 的动物的心率进一步显著降低（p<0.05）。
这些数据提供了临床前证据，表明 DEXMED 可能是 NLX 逆转阿片类药物后 METH 诱导激越的一种安全有效的化学约束手段。
