{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T18:47:50Z","timestamp":1790362070565,"version":"4.1.0"},"reference-count":44,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2019,6,1]],"date-time":"2019-06-01T00:00:00Z","timestamp":1559347200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2019,6,1]],"date-time":"2019-06-01T00:00:00Z","timestamp":1559347200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2019,5,7]],"date-time":"2019-05-07T00:00:00Z","timestamp":1557187200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010135","name":"Finska L\u00e4kares\u00e4llskapet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010135","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007797","name":"Helsingin Yliopisto","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007797","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003554","name":"Lundbeckfonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006306","name":"Sigrid Jus\u00e9liuksen S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006306","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Journal of Controlled Release"],"published-print":{"date-parts":[[2019,6]]},"DOI":"10.1016\/j.jconrel.2019.05.005","type":"journal-article","created":{"date-parts":[[2019,5,7]],"date-time":"2019-05-07T16:27:02Z","timestamp":1557246422000},"page":"29-38","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":143,"special_numbering":"C","title":["Dexmedetomidine enhances glymphatic brain delivery of intrathecally administered drugs"],"prefix":"10.1016","volume":"304","author":[{"given":"Tuomas O.","family":"Lilius","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"Blomqvist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie L.","family":"Hauglund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guojun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik Filip","family":"St\u00e6ger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"B\u00e6rentzen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fredrik","family":"Ahlstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janne T.","family":"Backman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eija A.","family":"Kalso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pekka V.","family":"Rauhala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maiken","family":"Nedergaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.jconrel.2019.05.005_bb0005","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1001\/jama.291.1.63","article-title":"Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial","volume":"291","author":"Staats","year":"2004","journal-title":"Jama"},{"key":"10.1016\/j.jconrel.2019.05.005_bb0010","doi-asserted-by":"crossref","first-page":"1898","DOI":"10.1056\/NEJMoa1712649","article-title":"Study of intraventricular cerliponase alfa for CLN2 disease","volume":"378","author":"Schulz","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0015","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1056\/NEJMoa1702752","article-title":"Nusinersen versus sham control in infantile-onset spinal muscular atrophy","volume":"377","author":"Finkel","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0020","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1021\/mp300495e","article-title":"Diffusion of macromolecules in the brain: implications for drug delivery","volume":"10","author":"Wolak","year":"2013","journal-title":"Mol. Pharm."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0025","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1126\/science.1240514","article-title":"Neuroscience. Garbage truck of the brain","volume":"340","author":"Nedergaard","year":"2013","journal-title":"Science"},{"key":"10.1016\/j.jconrel.2019.05.005_bb0030","doi-asserted-by":"crossref","first-page":"147ra111","DOI":"10.1126\/scitranslmed.3003748","article-title":"A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid \u03b2","volume":"4","author":"Iliff","year":"2012","journal-title":"Sci. Transl. Med."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0035","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1172\/jci.insight.120922","article-title":"Transcranial optical imaging reveals a pathway for optimizing the delivery of immunotherapeutics to the brain","volume":"3","author":"Plog","year":"2018","journal-title":"JCI Insight"},{"key":"10.1016\/j.jconrel.2019.05.005_bb0040","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1002\/ana.24271","article-title":"Impairment of paravascular clearance pathways in the aging brain","volume":"76","author":"Kress","year":"2014","journal-title":"Ann. Neurol."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0045","doi-asserted-by":"crossref","first-page":"74","DOI":"10.7554\/eLife.40070","article-title":"Aquaporin-4-dependent glymphatic solute transport in the rodent brain","volume":"7","author":"Mestre","year":"2018","journal-title":"Elife"},{"key":"10.1016\/j.jconrel.2019.05.005_bb0050","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1084\/jem.20142290","article-title":"A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules","volume":"212","author":"Aspelund","year":"2015","journal-title":"J. Exp. Med."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0055","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nature14432","article-title":"Structural and functional features of central nervous system lymphatic vessels","volume":"523","author":"Louveau","year":"2015","journal-title":"Nature"},{"key":"10.1016\/j.jconrel.2019.05.005_bb0060","doi-asserted-by":"crossref","first-page":"16180","DOI":"10.1523\/JNEUROSCI.3020-14.2014","article-title":"Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury","volume":"34","author":"Iliff","year":"2014","journal-title":"J. Neurosci."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0065","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1177\/0271678X16661202","article-title":"Glymphatic clearance controls state-dependent changes in brain lactate concentration","volume":"37","author":"Lundgaard","year":"2016","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0070","doi-asserted-by":"crossref","DOI":"10.1016\/j.lfs.2017.05.028","article-title":"The pathway of subarachnoid CSF moving into the spinal parenchyma and the role of astrocytic aquaporin-4 in this process","author":"Wei","year":"2017","journal-title":"Life Sci."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0075","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1126\/science.1241224","article-title":"Sleep drives metabolite clearance from the adult brain","volume":"342","author":"Xie","year":"2013","journal-title":"Science"},{"key":"10.1016\/j.jconrel.2019.05.005_bb0080","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.aav5447","article-title":"Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia","volume":"5","author":"Hablitz","year":"2019","journal-title":"Sci. Adv."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0085","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1007\/s40262-017-0507-7","article-title":"Clinical pharmacokinetics and pharmacodynamics of dexmedetomidine","volume":"56","author":"Weerink","year":"2017","journal-title":"Clin. Pharmacokinet."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0090","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0169525","article-title":"Dexmedetomidine versus midazolam in procedural sedation. A systematic review of efficacy and safety","volume":"12","author":"Barends","year":"2017","journal-title":"PLoS One"},{"key":"10.1016\/j.jconrel.2019.05.005_bb0095","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1097\/ALN.0000000000000841","article-title":"Clinical electroencephalography for anesthesiologists: part I: background and basic signatures","volume":"123","author":"Purdon","year":"2015","journal-title":"Anesthesiology"},{"key":"10.1016\/j.jconrel.2019.05.005_bb0100","doi-asserted-by":"crossref","DOI":"10.3791\/57378","article-title":"Cannula implantation into the cisterna magna of rodents","author":"Xavier","year":"2018","journal-title":"J. Vis. Exp."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0105","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.jpba.2015.04.044","volume":"114","author":"Moreno-Vicente","year":"2015","journal-title":"J. Pharm. Biomed. Anal."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0110","doi-asserted-by":"crossref","first-page":"44","DOI":"10.3389\/fninf.2014.00044","article-title":"The Insight ToolKit image registration framework","volume":"8","author":"Avants","year":"2014","journal-title":"Front Neuroinform."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0115","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1097\/ALN.0000000000001888","article-title":"Anesthesia with dexmedetomidine and low-dose isoflurane increases solute transport via the glymphatic pathway in rat brain when compared with high-dose isoflurane","volume":"127","author":"Benveniste","year":"2017","journal-title":"Anesthesiology"},{"key":"10.1016\/j.jconrel.2019.05.005_bb0120","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1093\/bja\/71.3.447","article-title":"Actions of the hypnotic anaesthetic, dexmedetomidine, on noradrenaline release and cell firing in rat locus coeruleus slices","volume":"71","author":"Jorm","year":"1993","journal-title":"Br. J. Anaesth."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0125","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1046\/j.1460-9568.2002.02014.x","article-title":"In vivo regulation of dopamine and noradrenaline release by alpha2A-adrenoceptors in the mouse prefrontal cortex","volume":"15","author":"Ihalainen","year":"2002","journal-title":"Eur. J. Neurosci."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0130","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-018-07318-3","article-title":"Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension","volume":"9","author":"Mestre","year":"2018","journal-title":"Nat. Commun."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0135","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1172\/JCI118214","article-title":"Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A","volume":"96","author":"Schinkel","year":"1995","journal-title":"J. Clin. Invest."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0140","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/sj.bjp.0702804","article-title":"The role of P-glycoprotein in blood-brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (\u2212\/\u2212) and mdr1a (+\/+) mice","volume":"128","author":"Xie","year":"1999","journal-title":"Br. J. Pharmacol."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0145","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S0169-409X(98)00085-4","article-title":"P-Glycoprotein, a gatekeeper in the blood-brain barrier","volume":"36","author":"Schinkel","year":"1999","journal-title":"Adv. Drug Deliv. Rev."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0150","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1021\/acs.molpharmaceut.7b00852","article-title":"Drug clearance from cerebrospinal fluid mediated by organic anion transporters 1 (Slc22a6) and 3 (Slc22a8) at arachnoid membrane of rats","volume":"15","author":"Zhang","year":"2018","journal-title":"Mol. Pharm."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0155","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1111\/j.1600-0773.1994.tb01068.x","article-title":"Liposolubility and protein binding of oxycodone in vitro","volume":"74","author":"P\u00f6yhi\u00e4","year":"1994","journal-title":"Pharmacol. Toxicol."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0160","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1097\/ALN.0b013e318164cf9e","article-title":"Blood-brain barrier transport helps to explain discrepancies in in vivo potency between oxycodone and morphine","volume":"108","author":"Bostr\u00f6m","year":"2008","journal-title":"Anesthesiology"},{"key":"10.1016\/j.jconrel.2019.05.005_bb0165","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1093\/bja\/aes344","article-title":"Efficacy of adding clonidine to intrathecal morphine in acute postoperative pain: meta-analysis","volume":"110","author":"Engelman","year":"2013","journal-title":"Br. J. Anaesth."},{"issue":"11","key":"10.1016\/j.jconrel.2019.05.005_bb0170","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1111\/cns.12172","article-title":"Effects of intravenous and intrathecal dexmedetomidine in spinal anesthesia: a meta-analysis","volume":"19","author":"Niu","year":"2013","journal-title":"CNS Neurosci. Ther."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0175","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/s12630-009-9231-6","article-title":"Intravenous dexmedetomidine, but not midazolam, prolongs bupivacaine spinal anesthesia","volume":"57","author":"Kaya","year":"2010","journal-title":"Can. J. Anesth."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0180","doi-asserted-by":"crossref","first-page":"342","DOI":"10.4103\/0970-9185.117101","article-title":"Intravenous dexmedetomidine versus clonidine for prolongation of bupivacaine spinal anesthesia and analgesia: a randomized double-blind study","volume":"29","author":"Reddy","year":"2013","journal-title":"J. Anaesthesiol. Clin. Pharmacol."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0185","doi-asserted-by":"crossref","first-page":"85","DOI":"10.4097\/kjae.2014.67.2.85","article-title":"The comparison of the effects of intravenous ketamine or dexmedetomidine infusion on spinal block with bupivacaine","volume":"67","author":"Kim","year":"2014","journal-title":"Korean J. Anesthesiol."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0190","first-page":"UC01","article-title":"Comparison of intravenous dexmedetomidine with midazolam in prolonging spinal anaesthesia with ropivacaine","volume":"11","author":"Rekhi","year":"2017","journal-title":"J. Clin. Diagn. Res."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0195","doi-asserted-by":"crossref","first-page":"46","DOI":"10.4103\/joacp.JOACP_132_16","article-title":"Effect of intravenous dexmedetomidine administered as bolus or as bolus-plus-infusion on subarachnoid anesthesia with hyperbaric bupivacaine","volume":"34","author":"Kavya","year":"2018","journal-title":"J. Anaesthesiol. Clin. Pharmacol."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0200","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1042\/CS20050101","article-title":"Alpha(2)-adrenergic receptor signalling in hypertension","volume":"109","author":"Kanagy","year":"2005","journal-title":"Clin. Sci."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0205","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1139\/y04-028","article-title":"Cardiovascular and parasympathetic effects of dexmedetomidine in healthy subjects","volume":"82","author":"Penttil\u00e4","year":"2004","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"10.1016\/j.jconrel.2019.05.005_bb0210","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1097\/00000542-200611000-00010","article-title":"Effects of low and high plasma concentrations of dexmedetomidine on myocardial perfusion and cardiac function in healthy male subjects","volume":"105","author":"Snapir","year":"2006","journal-title":"Anesthesiology"},{"key":"10.1016\/j.jconrel.2019.05.005_bb0215","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1097\/00000542-200008000-00016","article-title":"The effects of increasing plasma concentrations of dexmedetomidine in humans","volume":"93","author":"Ebert","year":"2000","journal-title":"Anesthesiology"},{"key":"10.1016\/j.jconrel.2019.05.005_bb0220","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.121537","article-title":"Brain-wide glymphatic enhancement and clearance in humans assessed with MRI","volume":"3","author":"Ringstad","year":"2018","journal-title":"JCI Insight"}],"container-title":["Journal of Controlled Release"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0168365919302536?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0168365919302536?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T15:39:56Z","timestamp":1759160396000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0168365919302536"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6]]},"references-count":44,"alternative-id":["S0168365919302536"],"URL":"https:\/\/doi.org\/10.1016\/j.jconrel.2019.05.005","relation":{},"ISSN":["0168-3659"],"issn-type":[{"value":"0168-3659","type":"print"}],"subject":[],"published":{"date-parts":[[2019,6]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Dexmedetomidine enhances glymphatic brain delivery of intrathecally administered drugs","name":"articletitle","label":"Article Title"},{"value":"Journal of Controlled Release","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.jconrel.2019.05.005","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2019 The Authors. Published by Elsevier B.V.","name":"copyright","label":"Copyright"}]}}