scholarly journals Two Studies on Reversal of Opioid-induced Respiratory Depression by BK-channel Blocker GAL021 in Human Volunteers

2014 ◽  
Vol 121 (3) ◽  
pp. 459-468 ◽  
Author(s):  
Margot Roozekrans ◽  
Rutger van der Schrier ◽  
Pieter Okkerse ◽  
Justin Hay ◽  
James F. McLeod ◽  
...  
Keyword(s):  
Respiratory Depression ◽  
Channel Blocker ◽  
Minute Ventilation ◽  
Bk Channel ◽  
Bkca Channel ◽  
High Dose ◽  
Double Blind ◽  
Safety Issues ◽  
Male Volunteers ◽  
Carotid Bodies

Abstract Background: Opioid-induced respiratory depression is potentially lethal. GAL021 is a calcium-activated potassium (BKCa) channel blocker that causes reversal of opioid-induced respiratory depression in animals due to a stimulatory effect on ventilation at the carotid bodies. To assess in humans whether GAL021 stimulates breathing in established opioid-induced respiratory depression and to evaluate its safety, a proof-of-concept double-blind randomized controlled crossover study on isohypercapnic ventilation (study 1) and subsequent double-blind exploratory study on poikilocapnic ventilation and nonrespiratory end points (study 2) was performed. Methods: In study 1, intravenous low- and high-dose GAL021 and placebo were administrated on top of low- and high-dose alfentanil-induced respiratory depression in 12 healthy male volunteers on two separate occasions. In study 2, the effect of GAL021/placebo on poikilocapnic ventilation, analgesia, and sedation were explored in eight male volunteers. Data are mean difference between GAL021 and placebo (95% CI). Results: Study 1: Under isohypercapnic conditions, a separation between GAL021 and placebo on minute ventilation was observed by 6.1 (3.6 to 8.6) l/min (P < 0.01) and 3.6 (1.5 to 5.7) l/min (P < 0.01) at low-dose alfentanil plus high-dose GAL021 and high-dose-alfentanil plus high-dose GAL021, respectively. Study 2: Similar observations were made on poikilocapnic ventilation and arterial pCO2. GAL021 had no effect on alfentanil-induced sedation, antinociception and no safety issues or hemodynamic effects became apparent. Conclusion: GAL021 produces respiratory stimulatory effects during opioid-induced respiratory depression with containment of opioid-analgesia and without any further increase of sedation. Further studies are needed to confirm these preliminary data.

Two Studies on Reversal of Opioid-Induced Respiratory Depression by BK-Channel Blocker GAL021 in Human Volunteers

2015 ◽  
Vol 59 (2) ◽  
pp. 92-93
Author(s):  
Margot Roozekrans ◽  
Rutger van der Schrier ◽  
Pieter Okkerse ◽  
Justin Hay ◽  
James F. McLeod ◽  
...  
Keyword(s):  
Respiratory Depression ◽  
Channel Blocker ◽  
Bk Channel ◽  
Human Volunteers

Ventilatory Response to Hypercapnia as Experimental Model to Study Effects of Oxycodone on Respiratory Depression

2021 ◽  
Vol 16 ◽  
Author(s):  
Lynn R. Webster ◽  
Erik Hansen ◽  
Gregory J. Stoddard ◽  
Austin Rynders ◽  
David Ostler ◽  
...  
Keyword(s):  
Respiratory Depression ◽  
Ventilatory Response ◽  
Volume Flow Rate ◽  
Minute Ventilation ◽  
Statistical Significance ◽  
Adult Males ◽  
Post Dose ◽  
Double Blind ◽  
End Tidal ◽  
End Tidal Co2

Background: Opioid analgesics used to treat pain can cause respiratory depression. However, this effect has not been extensively studied, and life- threatening, opioid-induced respiratory depression remains difficult to predict. We tested the ventilatory response to hypercapnia for evaluating the pharmacodynamic effect of a drug on respiratory depression. Methods: We conducted a randomized, placebo-controlled, double-blind, crossover, study in 12 healthy adult males. Subjects received 2 treatments (placebo and immediate-release oxycodone 30 mg) separated by a 24-hour washout period. Subjects inhaled a mixture of 7% carbon dioxide, 21% oxygen, and 72% nitrogen for 5 minutes to assess respiratory depression. Minute ventilation, respiratory rate, tidal volume, flow rate, end-tidal CO2, and oxygen saturation were recorded continuously at pre-dose and 30, 60, 120, and 180 minutes post-dose. The primary endpoint was the effect on ventilatory response to hypercapnia at 60 minutes post-dose, as assessed by the slope of the linear relationship between minute ventilation and end-tidal CO2. Results: At 60 minutes post-dose, subjects had a mean slope of 2.4 in the oxycodone crossover period, compared to 0.1 in the placebo period (mean difference, 2.3; 95%CI: 0.2 to 4.5; p = 0.035). Statistical significance was likewise achieved at the secondary time points (30, 120, and 180 minutes post-dose, p <0.05). Conclusions: This model for testing ventilatory response to hypercapnia discriminated the effect of 30 mg of oxycodone vs. placebo for up to 3 hours after a single dose. It may serve as a method to predict the relative effect of a drug on respiratory depression.

Effect of Flumazenil on Ventilatory Drive during Sedation with Midazolam and Alfentanil

1996 ◽  
Vol 85 (4) ◽  
pp. 713-720 ◽  
Author(s):  
Jeffrey B. Gross ◽  
Robert T. Blouin ◽  
Shaul Zandsberg ◽  
Pattilyn F. Conard ◽  
Jurgen Haussler
Keyword(s):  
Carbon Dioxide ◽  
Respiratory Depression ◽  
Minute Ventilation ◽  
Study Drug ◽  
Double Blind ◽  
Ventilatory Responses ◽  
Ventilatory Drive ◽  
To Receive ◽  
Blind Crossover Study ◽  
Double Blind Crossover Study

Background Patients who receive a combination of a benzodiazepine and an opioid for conscious sedation are at risk for developing respiratory depression. While flumazenil effectively antagonizes the respiratory depression associated with a benzodiazepine alone, its efficacy in the presence of both a benzodiazepine and an opioid has not been established. This study was designed to determine whether flumazenil can reverse benzodiazepine-induced depression of ventilatory drive in the presence of an opioid. Methods Twelve healthy volunteers completed this randomized, double-blind, crossover study. Ventilatory responses to carbon dioxide and to isocapnic hypoxia were determined during four treatment phases: (1) baseline, (2) alfentanil infusion; (3) combined midazolam and alfentanil infusions, and (4) combined alfentanil, midazolam, and "study drug" (consisting of either flumazenil or flumazenil vehicle) infusions. Subjects returned 2-6 weeks later to receive the alternate study drug. Results Alfentanil decreased the slope of the carbon dioxide response curve from 2.14 +/- 0.40 to 1.43 +/- 0.19 l.min-1.mmHg-1 (x +/- SE, P &lt; 0.05), and decreased the minute ventilation at P(ET)CO2 = 50 mmHg (VE50) from 19.7 +/- 1.2 to 14.8 +/- 0.9l.min-1 (P &lt; 0.05). Midazolam further reduced these variables to 0.87 +/- 0.17 l.min-1.mmHg-1 (P &lt; 0.05) and 11.7 +/- 0.8 l.min-1 (P &lt; 0.05), respectively. With addition of flumazenil, slope and VE50 increased to 1.47 +/- 0.37 l.min-1.mmHg-1 (P &lt; 0.05) and 16.4 +/- 2.0l.min-1 (P &lt; 0.05); after placebo, the respective values of 1.02 +/- 0.19 l.min-1.mmHg-1 and 12.5 +/- 1.2 l.min-1 did not differe significantly from their values during combined alfentanil and midazolam administration. The effect of flumazenil differed significantly from that of placebo (P &lt; 0.05). Both the slope and the displacement of the hypoxic ventilatory response, measured at P(ET)CO2 = 46 +/- 1 mmHG, were affected similarly, with flumazenil showing a significant improvement compared to placebo. Conclusions Flumazenil effectively reverses the benzodiazepine component of ventilatory depression during combined administration of a benzodiazepine and an opioid.

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