Dexmedetomidine enhances glymphatic brain delivery of intrathecally administered drugs

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http://hdl.handle.net/10138/307810

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Lilius , T O , Blomqvist , K , Hauglund , N , Liu , G , Stæger , F F , Bærentzen , S , Du , T , Ahlström , F , Backman , J T , Kalso , E , Rauhala , P V & Nedergaard , M 2019 , ' Dexmedetomidine enhances glymphatic brain delivery of intrathecally administered drugs ' , Journal of Controlled Release , vol. 304 , pp. 29-38 . https://doi.org/10.1016/j.jconrel.2019.05.005

Title: Dexmedetomidine enhances glymphatic brain delivery of intrathecally administered drugs
Author: Lilius, Tuomas O.; Blomqvist, Kim; Hauglund, Natalie; Liu, Guojun; Stæger, Frederik Filip; Bærentzen, Simone; Du, Ting; Ahlström, Fredrik; Backman, Janne T.; Kalso, Eija; Rauhala, Pekka V.; Nedergaard, Maiken
Contributor: University of Helsinki, Medicum
University of Helsinki, Department of Pharmacology
University of Helsinki, Doctoral Programme in Drug Research
University of Helsinki, HUSLAB
University of Helsinki, HUS Perioperative, Intensive Care and Pain Medicine
University of Helsinki, Pekka Rauhala / Principal Investigator
Date: 2019-06-28
Language: eng
Number of pages: 10
Belongs to series: Journal of Controlled Release
ISSN: 0168-3659
URI: http://hdl.handle.net/10138/307810
Abstract: Drug delivery to the central nervous system remains a major problem due to biological barriers. The blood-brainbarrier can be bypassed by administering drugs intrathecally directly to the cerebrospinal fluid (CSF). The glymphatic system, a network of perivascular spaces promoting fluid exchange between CSF and interstitial space, could be utilized to enhance convective drug delivery from the CSF to the parenchyma. Glymphatic flow is highest during sleep and anesthesia regimens that induce a slow-wave sleep-like state. Here, using mass spectrometry and fluorescent imaging techniques, we show that the clinically used alpha(2)-adrenergic agonist dexme-detomidine that enhances EEG slow-wave activity, increases brain and spinal cord drug exposure of intrathecally administered drugs in mice and rats. Using oxycodone, naloxone, and an IgG-sized antibody as relevant model drugs we demonstrate that modulation of glymphatic flow has a distinct impact on the distribution of intrathecally administered therapeutics. These findings can be exploited in the clinic to improve the efficacy and safety of intrathecally administered therapeutics.
Subject: 317 Pharmacy
Drug delivery
Glymphatic system
Pharmacokinetics
alpha(2)-adrenergic agonist
Dexmedetomidine
Opioid
Amyloid-beta
Antibody therapy
P-GLYCOPROTEIN
INTRAVENOUS DEXMEDETOMIDINE
NORADRENALINE RELEASE
PLASMA-CONCENTRATIONS
ANESTHESIA
CLEARANCE
PATHWAY
IMPAIRMENT
OXYCODONE
TRANSPORT
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