噻萘普汀能否拮抗阿片类诱导的呼吸抑制？动物实验与人体试验结果相反

本文由“小麻哥的日常"授权转载

摘要译文(供参考)

非典型三环类抗抑郁药噻萘普汀对阿片类药物诱导的呼吸抑制人体模型的呼吸作用

背景：

动物数据表明，抗抑郁剂和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体调节剂噻萘普汀能够预防阿片类药物引起的呼吸抑制。

这一假设是口服或静脉注射噻萘普汀可以有效预防或抵消阿片类药物引起的人类呼吸抑制。

方法：

健康男性和女性志愿者参加了两项随机、双盲、安慰剂对照、交叉设计的研究。

首先，对口服噻萘普汀（37.5、50和100 mg剂量，8名受试者）预处理，然后诱导阿芬太尼诱导的呼吸抑制（阿芬太尼靶浓度，100 ng/ml）进行测试。

主要结局终点是在推断的呼气末二氧化碳浓度为55 mmHg（V̇E55）时进行通气。

接下来，在15名志愿者中测定了随后四次递增的静脉滴注噻萘普汀（目标噻奈普汀血浆浓度400、1000、1500和2000 ng/ml，每次超过15分钟）对抗瑞芬太尼诱发的呼吸抑制的能力。

在等高碳酸血症时测量通气量（基线通气量20±2 l/min）。

主要结局终点是在噻萘普汀与安慰剂输注60分钟期间的分钟通气量。

结果：

安慰剂预处理后，阿芬太尼将V̇E55降低至13.7（95%CI，8.6至18.8）l/min，而在50 mg噻萘普汀预处理后将V̇Eۯ55降低至17.9（10.2至25.7）l/min（两组间的平均差异为4.2（-11.5至3.0）l/min），P=0.070）。

在500至2000 ng/ml的测量浓度范围内，静脉注射噻萘普汀不会刺激通气，反而加重了瑞芬太尼诱发的呼吸抑制：噻萘普汀9.6±0.8 l/min，安慰剂15.0±0.9 l/min；平均差值为5.3 l/min；95%CI为2.5至8.2 l/min；P＝0.001。

结论：

口服和静脉注射噻萘普汀都不是呼吸兴奋剂。

在500至2000纳克/毫升的浓度范围内静脉注射噻萘普汀可加重瑞芬太尼诱发的呼吸抑制。

原文摘要

Respiratory Effects of the Atypical Tricyclic Antidepressant Tianeptine in Human Models of Opioid-induced Respiratory Depression

Background:

Animal data suggest that the antidepressant and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor modulator tianeptine is able to prevent opioid-induced respiratory depression. The hypothesis was that oral or intravenous tianeptine can effectively prevent or counteract opioid-induced respiratory depression in humans.

Methods:

Healthy male and female volunteers participated in two studies that had a randomized, double blind, placebo-controlled, crossover design.

First, oral tianeptine (37.5-, 50-, and 100-mg doses with 8 subjects) pretreatment followed by induction of alfentanil-induced respiratory depression (alfentanil target concentration, 100 ng/ml) was tested.

Primary endpoint was ventilation at an extrapolated end-tidal carbon dioxide concentration of 55 mmHg (V̇E55).

Next, the ability of four subsequent and increasing infusions of intravenous tianeptine (target tianeptine plasma concentrations 400, 1,000, 1,500, and 2,000 ng/ml, each given over 15 min) to counteract remifentanil-induced respiratory depression was determined in 15 volunteers.

Ventilation was measured at isohypercpania (baseline ventilation 20 ± 2 l/min).

The primary endpoint was minute ventilation during the 60 min of tianeptine versus placebo infusion.

Results: 

Alfentanil reduced V̇E55 to 13.7 (95% CI, 8.6 to 18.8) l/min after placebo pretreatment and to 17.9 (10.2 to 25.7) l/min after 50-mg tianeptine pretreatment (mean difference between treatments 4.2 (-11.5 to 3.0) l/min, P = 0.070). Intravenous tianeptine in the measured concentration range of 500 to 2,000 ng/ml did not stimulate ventilation but instead worsened remifentanil-induced respiratory depression: tianeptine, 9.6 ± 0.8 l/min versus placebo 15.0 ± 0.9 l/min; mean difference, 5.3 l/min; 95% CI, 2.5 to 8.2 l/min; P = 0.001, after 1 h of treatment.

Conclusions: 

Neither oral nor intravenous tianeptine were respiratory stimulants. Intravenous tianeptine over the concentration range of 500 to 2000 ng/ml worsened respiratory depression induced by remifentanil.

原文

Algera H, van der Schrier R, Cavalla D, van Velzen M, Roozekrans M, McMorn A, Snape M, Horrigan JP, Evans S, Kiernan B, Sarton E, Olofsen E, Niesters M, Dahan A. Respiratory Effects of the Atypical Tricyclic Antidepressant Tianeptine in Human Models of Opioid-induced Respiratory Depression. Anesthesiology. 2022 Oct 1;137(4):446-458. doi: 10.1097/ALN.0000000000004324. PMID: 35867853.

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