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High-dose naloxone,...
High-dose naloxone, an experimental tool uncovering latent sensitisation : pharmacokinetics in humans
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- Papathanasiou, Theodoros (författare)
- University of Copenhagen
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- Springborg, Anders Deichmann (författare)
- Copenhagen University Hospital
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- Kongstad, Kenneth Thermann (författare)
- University of Copenhagen
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- Staerk, Dan (författare)
- University of Copenhagen
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- Møller, Kirsten (författare)
- Copenhagen University Hospital
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- Taylor, Bradley Kenneth (författare)
- University of Kentucky
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- Lund, Trine Meldgaard (författare)
- University of Copenhagen
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- Werner, Mads Utke (författare)
- Lund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,Copenhagen University Hospital
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(creator_code:org_t)
- Elsevier BV, 2019
- 2019
- Engelska.
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Ingår i: British Journal of Anaesthesia. - : Elsevier BV. - 0007-0912. ; 123:2, s. 204-214
- Relaterad länk:
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http://dx.doi.org/10...
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http://bjanaesthesia...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Background: Naloxone, an opioid receptor antagonist, is used as a pharmacological tool to detect tonic endogenous activation of opioid receptors in experimental pain models. We describe a pharmacokinetic model linking naloxone pharmacokinetics to its main metabolite after high-dose naloxone infusion. Methods: Eight healthy volunteers received a three-stage stepwise high-dose i.v. naloxone infusion (total dose 3.25 mg kg−1). Naloxone and naloxone-3-glucuronide (N3G) plasma concentrations were sampled from infusion onset to 334 min after infusion discontinuation. Pharmacokinetic analysis was performed using non-linear mixed effect models (NONMEM). The predictive performances of Dowling's and Yassen's models were evaluated, and target-controlled infusion simulations were performed. Results: Three- and two-compartment disposition models with linear elimination kinetics described the naloxone and N3G concentration time-courses, respectively. Two covariate models were developed: simple (weight proportional) and complex (with the shallow peripheral volume of distribution linearly increasing with body weight). The median prediction error (MDPE) and wobble for Dowling's model were –32.5% and 33.4%, respectively. For Yassen's model, the MDPE and wobble were 1.2% and 19.9%, respectively. Conclusions: A parent–metabolite pharmacokinetic model was developed for naloxone and N3G after high-dose naloxone infusion. No saturable pharmacokinetics were observed. Whereas Dowling's model was inaccurate and over-predicted naloxone concentrations, Yassen's model accurately predicted naloxone pharmacokinetics. The newly developed covariate models may be used for high-dose TCI-naloxone for experimental and clinical practice. Clinical trials registration: NCT01992146.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Anestesi och intensivvård (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Anesthesiology and Intensive Care (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Nyckelord
- central sensitisation
- chronic pain
- endogenous opioids
- naloxone
- opioid receptor antagonist
- pharmacokinetics
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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