期刊
JOURNAL OF CONTROLLED RELEASE
卷 304, 期 -, 页码 29-38出版社
ELSEVIER
DOI: 10.1016/j.jconrel.2019.05.005
关键词
Drug delivery; Glymphatic system; Pharmacokinetics; alpha(2)-adrenergic agonist; Dexmedetomidine; Opioid; Amyloid-beta; Antibody therapy
资金
- Lundbeck Foundation
- Novo Nordisk Foundation
- Sigrid Juselius Foundation
- Finska Lakaresallskapet
- University of Helsinki Research Funds
- European Union's Horizon 2020 research and innovation programme under the Marie SklodowskaCurie grant [798944]
- Marie Curie Actions (MSCA) [798944] Funding Source: Marie Curie Actions (MSCA)
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.
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