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Research ArticleArticle

Anesthetic Profile of Dexmedetomidine Identified by Stimulus-Response and Continuous Measurements in Rats

Cornelis J. J. G. Bol, John P. W. Vogelaar and Jaap W. Mandema
Journal of Pharmacology and Experimental Therapeutics October 1999, 291 (1) 153-160;
Cornelis J. J. G. Bol
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John P. W. Vogelaar
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Jaap W. Mandema
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Abstract

This study characterizes the anesthetic profile of dexmedetomidine on the basis of steady-state plasma concentrations using defined stimulus-response, ventilatory, and continuous electroencephalographic (EEG) and cardiovascular effect measures in rats. At constant plasma concentrations of dexmedetomidine (range, 0.5–19 ng/ml), targeted and maintained by target-controlled infusion, the whisker reflex, righting reflex, startle reflex (to noise), tail clamp response, hot water tail-flick latency, and attenuation of heart rate (HR) increase associated with tail-flick (sympathoadrenal block) and corneal reflex, were assessed in 22 rats. EEG (power in 0.5- to 3.5-Hz frequency band), mean arterial pressure, and HR were recorded continuously. Blood gas values and arterial drug concentrations were determined regularly. The following steady-state plasma EC50 values of dexmedetomidine (mean ± S.E. nanograms per milliter) were estimated: HR decrease (0.51 ± 0.04), EEG (1.02 ± 0.08), whisker reflex (1.09 ± 0.10), sympathoadrenal block (1.85 ± 0.80), mean arterial blood pressure increase (1.99 ± 0.44), righting reflex (2.13 ± 0.15), tail-flick latency (3.65 ± 0.87), startle reflex (3.75 ± 0.64), tail clamp (5.49 ± 1.34), and corneal reflex (24.5 ± 12.3). At the EC50value of tail clamp, ventilatory depression was minor. In rats, dexmedetomidine creates bradycardia, sedation/hypnosis, sympathoadrenal blocking effects, and blood pressure-increasing effects at plasma concentrations below 2.5 ng/ml. Higher plasma concentrations are needed to loose the startle reflex, tail-flick, tail clamp, and corneal reflex responses. Ventilatory depressant effects are minor. The applied EEG measure seems to reflect sedation/hypnosis but seems to have limited value to predict the deeper levels of analgesia and anesthesia of dexmedetomidine.

Footnotes

  • Send reprint requests to: Cornelis J. J. G. Bol, Ph.D., Department of Clinical Pharmacokinetics, Janssen Pharmaceutica, B-2340 Beerse, Belgium. E-mail: kbol{at}janbe.jnj.com

  • ↵1 This research was conducted at the Department of Anesthesia, Stanford University School of Medicine, Stanford, CA. This study was supported in part by National Institutes of Health Shannon Award GM-51309.

  • ↵2 Present address: Department of Clinical Pharmacokinetics, Janssen Pharmaceutica, Beerse, Belgium.

  • ↵3 Present address: Department of Anesthesiology, Leiden University Medical Center, Leiden, the Netherlands.

  • ↵4 Present address: Pharsight Corporation, Mountain View, CA.

  • Abbreviations:
    EEG
    electroencephalographic
    MAP
    mean arterial blood pressure
    SBP
    systolic blood pressure
    LC
    locus ceruleus
    PD
    pharmacodynamic
    TCI
    target-controlled infusion
    • Received February 25, 1999.
    • Accepted June 29, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 1
1 Oct 1999
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Research ArticleArticle

Anesthetic Profile of Dexmedetomidine Identified by Stimulus-Response and Continuous Measurements in Rats

Cornelis J. J. G. Bol, John P. W. Vogelaar and Jaap W. Mandema
Journal of Pharmacology and Experimental Therapeutics October 1, 1999, 291 (1) 153-160;

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Research ArticleArticle

Anesthetic Profile of Dexmedetomidine Identified by Stimulus-Response and Continuous Measurements in Rats

Cornelis J. J. G. Bol, John P. W. Vogelaar and Jaap W. Mandema
Journal of Pharmacology and Experimental Therapeutics October 1, 1999, 291 (1) 153-160;
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