A Novel Strategy to Reverse General Anesthesia by Scavenging with the Acyclic Cucurbit[n]uril-type Molecular Container Calabadion 2.
A Novel Strategy to Reverse General Anesthesia by Scavenging with the Acyclic Cucurbit[n]uril-type Molecular Container Calabadion 2.
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DOI：
10.1097/aln.0000000000001199
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发表时间：
2016-08
期刊：
影响因子：
8.8
通讯作者：
Eikermann M
中科院分区：
文献类型：
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作者：
Diaz-Gil D;Haerter F;Falcinelli S;Ganapati S;Hettiarachchi GK;Simons JC;Zhang B;Grabitz SD;Moreno Duarte I;Cotten JF;Eikermann-Haerter K;Deng H;Chamberlin NL;Isaacs L;Briken V;Eikermann M
Calabadion 2是一种新型药物包封剂。在这项研究中，我们的目的是评估其作为一种药物逆转全身麻醉与依托咪酯和氯胺酮，促进恢复的效用。为了评价calabadion 2对麻醉恢复的影响，我们研究了大鼠连续静脉注射依托咪酯或氯胺酮和肌肉注射氯胺酮后对calabadion 2的反应。我们测量了麻醉深度的脑电图预测指标（爆发抑制比和总脑电图功率）、功能活动障碍、血压和毒性。Calabadion 2可剂量依赖性地逆转氯胺酮和依托咪酯对麻醉深度和药物性低血压的脑电图预测指标的影响，并缩短翻正反射和功能活动的恢复时间。Calabadion 2在3-（4,5-二甲基噻唑-2-基）-5-（3-羧基甲氧基苯基）-2-（4-巯基）- 2h -四唑基细胞活力和腺苷酸激酶释放细胞坏死试验中显示出低细胞毒性，不抑制人醚-à-go-go-related通道，也不具有诱变性（Ames试验）。根据最大耐受剂量和翻正反射恢复速度，我们计算出氯胺酮逆转的calabadion 2在恢复中的治疗指数为16:1(95%可信区间[CI]， 10-26:1)，依托咪酯逆转的治疗指数为3:1 （95% CI, 2 - 5:1）。Calabadion 2以无毒浓度化学包封逆转依托咪酯和氯胺酮麻醉。
Calabadion 2 is a new drug-encapsulating agent. In this study, we aim to assess its utility as an agent to reverse general anesthesia with etomidate and ketamine and facilitate recovery. To evaluate the effect of calabadion 2 on anesthesia recovery, we studied the response of rats to calabadion 2 following continuous and bolus intravenous etomidate or ketamine and bolus intramuscular ketamine administration. We measured electroencephalographic predictors of depth of anesthesia (burst suppression ratio and total electroencephalographic power), functional mobility impairment, blood pressure, and toxicity. Calabadion 2 dose-dependently reverses the effects of ketamine and etomidate on electroencephalographic predictors of depth of anesthesia, as well as drug-induced hypotension, and shortens the time to recovery of righting reflex and functional mobility. Calabadion 2 displayed low cytotoxicity in 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium-based cell viability and adenylate kinase release cell necrosis assays, did not inhibit the human ether-à-go-go-related channel, and was not mutagenic (Ames test). Based on maximum tolerable dose and acceleration of righting reflex recovery, we calculated the therapeutic index of calabadion 2 in recovery as 16:1 (95% confidence interval [CI], 10–26:1) for the reversal of ketamine and 3:1 (95% CI, 2–5:1) for the reversal of etomidate. Calabadion 2 reverses etomidate and ketamine anesthesia in rats by chemical encapsulation at non-toxic concentrations.