Smith Mark A, Biancorosso Samantha L, Camp Jacob D, Hailu Salome H, Johansen Alexandra N, Morris Mackenzie H, Carlson Hannah N
Department of Psychology and Program in Neuroscience, Davidson College, Davidson, NC, United States.
Front Pharmacol. 2023 Oct 26;14:1280289. doi: 10.3389/fphar.2023.1280289. eCollection 2023.
The recreational use of fentanyl in combination with xylazine (i.e., "tranq-dope") represents a rapidly emerging public health threat characterized by significant toxicity and mortality. This study quantified the interactions between these drugs on lethality and examined the effectiveness of potential rescue medications to prevent a lethal overdose. Male and female mice were administered acute doses of fentanyl, xylazine, or their combination via intraperitoneal injection, and lethality was determined 0.5, 1.0, 1.5, 2.0, and 24 h after administration. Both fentanyl and xylazine produced dose-dependent increases in lethality when administered alone. A nonlethal dose of fentanyl (56 mg/kg) produced an approximately 5-fold decrease in the estimated LD50 for xylazine (i.e., the dose estimated to produce lethality in 50% of the population). Notably, a nonlethal dose of xylazine (100 mg/kg) produced an approximately 100-fold decrease in the estimated LD for fentanyl. Both drug combinations produced a synergistic interaction as determined via isobolographic analysis. The opioid receptor antagonist, naloxone (3 mg/kg), but not the alpha-2 adrenergic receptor antagonist, yohimbine (3 mg/kg), significantly decreased the lethality of a fentanyl-xylazine combination. Lethality was rapid, with death occurring within 10 min after a high dose combination and generally within 30 min at lower dose combinations. Males were more sensitive to the lethal effects of fentanyl-xylazine combinations under some conditions suggesting biologically relevant sex differences in sensitivity to fentanyl-xylazine lethality. These data provide the first quantification of the lethal effects of "tranq-dope" and suggest that rapid administration of naloxone may be effective at preventing death following overdose.
芬太尼与赛拉嗪联合用于娱乐用途（即“镇静剂-毒品”）构成了一种迅速出现的公共卫生威胁，其特点是具有显著的毒性和死亡率。本研究对这些药物之间在致死性方面的相互作用进行了量化，并考察了潜在抢救药物预防致死性过量用药的有效性。通过腹腔注射给予雄性和雌性小鼠急性剂量的芬太尼、赛拉嗪或它们的组合，给药后0.5、1.0、1.5、2.0和24小时测定致死率。单独给药时，芬太尼和赛拉嗪均产生剂量依赖性的致死率增加。非致死剂量的芬太尼（56毫克/千克）使赛拉嗪的估计半数致死量（即估计能使50%的群体产生致死性的剂量）降低了约5倍。值得注意的是，非致死剂量的赛拉嗪（100毫克/千克）使芬太尼的估计致死剂量降低了约100倍。通过等效应线图分析确定，两种药物组合均产生协同相互作用。阿片受体拮抗剂纳洛酮（3毫克/千克）能显著降低芬太尼-赛拉嗪组合的致死率，但α-2肾上腺素能受体拮抗剂育亨宾（3毫克/千克）则不能。致死速度很快，高剂量组合后10分钟内死亡，较低剂量组合时一般在30分钟内死亡。在某些情况下，雄性对芬太尼-赛拉嗪组合的致死效应更敏感，这表明在对芬太尼-赛拉嗪致死性的敏感性方面存在生物学上相关的性别差异。这些数据首次对“镇静剂-毒品”的致死效应进行了量化，并表明快速给予纳洛酮可能有效预防过量用药后的死亡。
