Dexmedetomidine enhances glymphatic brain delivery of intrathecally administered drugs

JOURNAL OF CONTROLLED RELEASE

卷:304

Article

Lilius, Tuomas O.^1,2,3,4  Blomqvist, Kim^2,4  Hauglund, Natalie L.¹  Liu, Guojun⁵  Staeger, Frederik Filip¹  Baerentzen, Simone¹  Du, Ting⁵  Ahlstrom, Fredrik^2,4  Backman, Janne T.^3,4  Kalso, Eija A.^2,6  Rauhala, Pekka, V^2,4  Nedergaard, Maiken^1,3 

[1] Univ Copenhagen, Fac Hlth & Med Sci, Ctr Translat Neuromed, Copenhagen, Denmark

[2] Univ Helsinki, Fac Med, Dept Pharmacol, Helsinki, Finland

[3] Univ Helsinki, Helsinki Univ Hosp, Fac Med, Dept Clin Pharmacol, Helsinki, Finland

[4] Univ Helsinki, Fac Med, Individualized Drug Therapy Res Program, Helsinki, Finland

[5] Univ Rochester, Med Ctr, Ctr Translat Neuromed, Rochester, NY 14642 USA

[6] Univ Helsinki, Dept Anaesthesiol Intens Care Med & Pain Med, Helsinki Univ Hosp, Helsinki, Finland

关键词: Drug delivery;    Glymphatic system;    Pharmacokinetics;    alpha(2)-adrenergic agonist;    Dexmedetomidine;    Opioid;    Amyloid-beta;    Antibody therapy;   

DOI  :  10.1016/j.jconrel.2019.05.005

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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