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 organization: | Medicum Department of Pharmacology Faculty of Medicine University of Helsinki Department of Clinical Pharmacology INDIVIDRUG - Individualized Drug Therapy Research Programs Unit Doctoral Programme in Drug Research HUSLAB Janne Backman / Principal Investigator University Management HUS Perioperative, Intensive Care and Pain Medicine Eija Kalso / Principal Investigator Department of Diagnostics and Therapeutics Anestesiologian yksikkö Pekka Rauhala / Principal Investigator |
Date: | 2019-06-28 |
Language: | eng |
Number of pages: | 10 |
Belongs to series: | Journal of Controlled Release |
ISSN: | 0168-3659 |
DOI: | https://doi.org/10.1016/j.jconrel.2019.05.005 |
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 |
Peer reviewed: | Yes |
Rights: | cc_by_nc_nd |
Usage restriction: | openAccess |
Self-archived version: | publishedVersion |
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