{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T15:12:41Z","timestamp":1781795561563,"version":"3.54.5"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2014,7,2]],"date-time":"2014-07-02T00:00:00Z","timestamp":1404259200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["EJNMMI Res"],"published-print":{"date-parts":[[2014,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Abnormal behaviors of young patients after taking the anti-influenza agent oseltamivir (Tamiflu\u00ae, F. Hoffmann-La Roche, Ltd., Basel, Switzerland) have been suspected as neuropsychiatric adverse events (NPAEs). Immune response to viral infection is suspected to cause elevation of drug concentration in the brain of adolescents. In the present study, the effect of innate immune activation on the brain uptake of [<jats:sup>11<\/jats:sup>C]oseltamivir was quantitatively evaluated in juvenile monkeys.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Three 2-year-old monkeys underwent positron emission tomography (PET) scans at baseline and immune-activated conditions. Both scans were conducted under pre-dosing of clinically relevant oseltamivir. The immune activation condition was induced by the intravenous administration of polyinosine-polycytidylic acid (poly I:C). Dynamic [<jats:sup>11<\/jats:sup>C]oseltamivir PET scan and serial arterial blood sampling were performed to obtain [<jats:sup>11<\/jats:sup>C]oseltamivir kinetics. Brain uptake of [<jats:sup>11<\/jats:sup>C]oseltamivr was evaluated by its normalized brain concentration, brain-to-plasma concentration ratio, and plasma-to-brain transfer rate. Plasma pro-inflammatory cytokine levels were also measured.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Plasma interleukin-6 was elevated after intravenous administration of poly I:C in all monkeys. Brain radioactivity was uniform both at baseline and under poly I:C treatment. The mean brain concentrations of [<jats:sup>11<\/jats:sup>C]oseltamivir were 0.0033 and 0.0035% ID\/cm<jats:sup>3<\/jats:sup>\u2009\u00d7\u2009kg, the mean brain-to-plasma concentration ratios were 0.58 and 0.65, and the plasma-to-brain transfer rates were 0.0047 and 0.0051\u00a0mL\/min\/cm<jats:sup>3<\/jats:sup> for baseline and poly I:C treatment, respectively. Although these parameters were slightly changed by immune activation, the change was not notable.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>The brain uptake of [<jats:sup>11<\/jats:sup>C]oseltamivir was unchanged by poly I:C treatment in juvenile monkeys. This study demonstrated that the innate immune response similar to the immune activation of influenza would not notably change the brain concentration of oseltamivir in juvenile monkeys.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s13550-014-0024-8","type":"journal-article","created":{"date-parts":[[2014,7,1]],"date-time":"2014-07-01T21:07:46Z","timestamp":1404248866000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Evaluation of [11C]oseltamivir uptake into the brain during immune activation by systemic polyinosine-polycytidylic acid injection: a quantitative PET study using juvenile monkey models of viral infection"],"prefix":"10.1186","volume":"4","author":[{"given":"Chie","family":"Seki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arata","family":"Oh-Nishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Nagai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takafumi","family":"Minamimoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru","family":"Obayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Higuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Takei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Furutsuka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takehito","family":"Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Rong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mototsugu","family":"Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumito","family":"Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Kusuhara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Sugiyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuya","family":"Suhara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2014,7,2]]},"reference":[{"key":"24_CR1","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1097\/01.inf.0000219363.24938.62","volume":"25","author":"A Okumura","year":"2006","unstructured":"1. Okumura A, Kubota T, Kato T, Morishima T: Oseltamivir and delirious behavior in children with influenza. Pediatr Infect Dis J 2006, 25: 572.","journal-title":"Pediatr Infect Dis J"},{"key":"24_CR2","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1124\/dmd.107.017699","volume":"36","author":"K Morimoto","year":"2008","unstructured":"Morimoto K, Nakakariya M, Shirasaka Y, Kakinuma C, Fujita T, Tamai I, Ogihara T: Oseltamivir (Tamiflu) efflux transport at the blood\u2013brain barrier via P-glycoprotein. Drug Metab Dispos 2008, 36: 6\u20139. 10.1124\/dmd.107.017699","journal-title":"Drug Metab Dispos"},{"key":"24_CR3","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1124\/dmd.107.018556","volume":"36","author":"A Ose","year":"2008","unstructured":"Ose A, Kusuhara H, Yamatsugu K, Kanai M, Shibasaki M, Fujita T, Yamamoto A, Sugiyama Y: P-glycoprotein restricts the penetration of oseltamivir across the blood\u2013brain barrier. Drug Metab Dispos 2008, 36: 427\u2013434. 10.1124\/dmd.107.018556","journal-title":"Drug Metab Dispos"},{"key":"24_CR4","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/j.nucmedbio.2008.10.008","volume":"36","author":"A Hatori","year":"2009","unstructured":"Hatori A, Arai T, Yanamoto K, Yamasaki T, Kawamura K, Yui J, Konno F, Nakao R, Suzuki K, Zhang MR: Biodistribution and metabolism of the anti-influenza drug [11C]oseltamivir and its active metabolite [11C]Ro 64\u20130802 in mice. Nucl Med Biol 2009, 36: 47\u201355. 10.1016\/j.nucmedbio.2008.10.008","journal-title":"Nucl Med Biol"},{"key":"24_CR5","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1124\/dmd.108.024018","volume":"37","author":"A Ose","year":"2009","unstructured":"Ose A, Ito M, Kusuhara H, Yamatsugu K, Kanai M, Shibasaki M, Hosokawa M, Schuetz JD, Sugiyama Y: Limited brain distribution of [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64\u20130802), a pharmacologically active form of oseltamivir, by active efflux across the blood\u2013brain barrier mediated by organic anion transporter 3 (Oat3\/Slc22a8) and multidrug resistance-associated protein 4 (Mrp4\/Abcc4). Drug Metab Dispos 2009, 37: 315\u2013321. 10.1124\/dmd.108.024018","journal-title":"Drug Metab Dispos"},{"key":"24_CR6","doi-asserted-by":"publisher","first-page":"3687","DOI":"10.1128\/AAC.00327-08","volume":"52","author":"SS Jhee","year":"2008","unstructured":"Jhee SS, Yen M, Ereshefsky L, Leibowitz M, Schulte M, Kaeser B, Boak L, Patel A, Hoffmann G, Prinssen EP, Rayner CR: Low penetration of oseltamivir and its carboxylate into cerebrospinal fluid in healthy Japanese and Caucasian volunteers. Antimicrob Agents Chemother 2008, 52: 3687\u20133693. 10.1128\/AAC.00327-08","journal-title":"Antimicrob Agents Chemother"},{"key":"24_CR7","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.neulet.2011.03.055","volume":"495","author":"A Hatori","year":"2011","unstructured":"Hatori A, Yui J, Yanamoto K, Yamasaki T, Kawamura K, Takei M, Arai T, Fukumura T, Zhang MR: Determination of radioactivity in infant, juvenile and adult rat brains after injection of anti-influenza drug [(11)C]oseltamivir using PET and autoradiography. Neurosci Lett 2011, 495: 187\u2013191. 10.1016\/j.neulet.2011.03.055","journal-title":"Neurosci Lett"},{"key":"24_CR8","doi-asserted-by":"publisher","first-page":"950","DOI":"10.2967\/jnumed.110.083949","volume":"52","author":"T Takashima","year":"2011","unstructured":"Takashima T, Yokoyama C, Mizuma H, Yamanaka H, Wada Y, Onoe K, Nagata H, Tazawa S, Doi H, Takahashi K, Morita M, Kanai M, Shibasaki M, Kusuhara H, Sugiyama Y, Onoe H, Watanabe Y: Developmental changes in P-glycoprotein function in the blood\u2013brain barrier of nonhuman primates: PET study with R-11C-verapamil and 11C-oseltamivir. J Nucl Med 2011, 52: 950\u2013957. 10.2967\/jnumed.110.083949","journal-title":"J Nucl Med"},{"key":"24_CR9","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.2165\/0002018-200831120-00006","volume":"31","author":"S Toovey","year":"2008","unstructured":"Toovey S, Rayner C, Prinssen E, Chu T, Donner B, Thakrar B, Dutkowski R, Hoffmann G, Breidenbach A, Lindemann L, Carey E, Boak L, Gieschke R, Sacks S, Solsky J, Small I, Reddy D: Assessment of neuropsychiatric adverse events in influenza patients treated with oseltamivir: a comprehensive review. Drug Saf 2008, 31: 1097\u20131114. 10.2165\/0002018-200831120-00006","journal-title":"Drug Saf"},{"key":"24_CR10","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1007\/s10571-009-9431-1","volume":"30","author":"B Poller","year":"2010","unstructured":"Poller B, Drewe J, Krahenbuhl S, Huwyler J, Gutmann H: Regulation of BCRP (ABCG2) and P-glycoprotein (ABCB1) by cytokines in a model of the human blood\u2013brain barrier. Cell Mol Neurobiol 2010, 30: 63\u201370. 10.1007\/s10571-009-9431-1","journal-title":"Cell Mol Neurobiol"},{"key":"24_CR11","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.1124\/jpet.106.111807","volume":"319","author":"D Shi","year":"2006","unstructured":"Shi D, Yang J, Yang D, LeCluyse EL, Black C, You L, Akhlaghi F, Yan B: Anti-influenza prodrug oseltamivir is activated by carboxylesterase human carboxylesterase 1, and the activation is inhibited by antiplatelet agent clopidogrel. J Pharmacol Exp Ther 2006, 319: 1477\u20131484. 10.1124\/jpet.106.111807","journal-title":"J Pharmacol Exp Ther"},{"key":"24_CR12","doi-asserted-by":"publisher","first-page":"686","DOI":"10.1124\/mol.107.036889","volume":"72","author":"J Yang","year":"2007","unstructured":"Yang J, Shi D, Yang D, Song X, Yan B: Interleukin-6 alters the cellular responsiveness to clopidogrel, irinotecan, and oseltamivir by suppressing the expression of carboxylesterases HCE1 and HCE2. Mol Pharmacol 2007, 72: 686\u2013694. 10.1124\/mol.107.036889","journal-title":"Mol Pharmacol"},{"key":"24_CR13","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1016\/j.biopsych.2013.06.025","volume":"75","author":"MD Bauman","year":"2014","unstructured":"Bauman MD, Iosif AM, Smith SE, Bregere C, Amaral DG, Patterson PH: Activation of the maternal immune system during pregnancy alters behavioral development of Rhesus monkey offspring. Biol Psychiatry 2014, 75: 332\u2013341. 10.1016\/j.biopsych.2013.06.025","journal-title":"Biol Psychiatry"},{"key":"24_CR14","doi-asserted-by":"publisher","first-page":"2327","DOI":"10.1128\/MCB.10.5.2327","volume":"10","author":"TA Libermann","year":"1990","unstructured":"Libermann TA, Baltimore D: Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. Mol Cell Biol 1990, 10: 2327\u20132334.","journal-title":"Mol Cell Biol"},{"key":"24_CR15","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1128\/iai.34.2.416-421.1981","volume":"34","author":"HB Levy","year":"1981","unstructured":"Levy HB, Riley FL, Lvovsky E, Stephen EE: Interferon induction in primates by stabilized polyriboinosinic acid-polyribocytidylic acid: effect of component size. Infect Immun 1981, 34: 416\u2013421.","journal-title":"Infect Immun"},{"key":"24_CR16","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/S0969-8043(00)00392-4","volume":"55","author":"M Takei","year":"2001","unstructured":"Takei M, Kida T, Suzuki K: Sensitive measurement of positron emitters eluted from HPLC. Appl Radiat Isot 2001, 55: 229\u2013234. 10.1016\/S0969-8043(00)00392-4","journal-title":"Appl Radiat Isot"},{"key":"24_CR17","first-page":"G36","volume":"264","author":"M Yamazaki","year":"1993","unstructured":"Yamazaki M, Suzuki H, Hanano M, Tokui T, Komai T, Sugiyama Y: Na(+)-independent multispecific anion transporter mediates active transport of pravastatin into rat liver. Am J Physiol 1993, 264: G36-G44.","journal-title":"Am J Physiol"},{"key":"24_CR18","first-page":"1531","volume":"47","author":"Y Ikoma","year":"2006","unstructured":"Ikoma Y, Takano A, Ito H, Kusuhara H, Sugiyama Y, Arakawa R, Fukumura T, Nakao R, Suzuki K, Suhara T: Quantitative analysis of 11C-verapamil transfer at the human blood\u2013brain barrier for evaluation of P-glycoprotein function. J Nucl Med 2006, 47: 1531\u20131537.","journal-title":"J Nucl Med"},{"key":"24_CR19","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1124\/jpet.105.088328","volume":"316","author":"YJ Lee","year":"2006","unstructured":"Lee YJ, Maeda J, Kusuhara H, Okauchi T, Inaji M, Nagai Y, Obayashi S, Nakao R, Suzuki K, Sugiyama Y, Suhara T: In vivo evaluation of P-glycoprotein function at the blood\u2013brain barrier in nonhuman primates using [11C]verapamil. J Pharmacol Exp Ther 2006, 316: 647\u2013653. 10.1124\/jpet.105.088328","journal-title":"J Pharmacol Exp Ther"},{"key":"24_CR20","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1161\/01.RES.37.6.707","volume":"37","author":"JO Eichling","year":"1975","unstructured":"Eichling JO, Raichle ME, Grubb RL Jr, Larson KB, Ter-Pogossian MM: In vivo determination of cerebral blood volume with radioactive oxygen-15 in the monkey. Circ Res 1975, 37: 707\u2013714. 10.1161\/01.RES.37.6.707","journal-title":"Circ Res"},{"key":"24_CR21","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1038\/ni.1863","volume":"11","author":"T Kawai","year":"2010","unstructured":"Kawai T, Akira S: The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010, 11: 373\u2013384. 10.1038\/ni.1863","journal-title":"Nat Immunol"},{"key":"24_CR22","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1002\/jmv.1045","volume":"64","author":"L Kaiser","year":"2001","unstructured":"Kaiser L, Fritz RS, Straus SE, Gubareva L, Hayden FG: Symptom pathogenesis during acute influenza: interleukin-6 and other cytokine responses. J Med Virol 2001, 64: 262\u2013268. 10.1002\/jmv.1045","journal-title":"J Med Virol"},{"key":"24_CR23","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1002\/(SICI)1096-9071(199908)58:4<420::AID-JMV16>3.0.CO;2-T","volume":"58","author":"Y Ito","year":"1999","unstructured":"Ito Y, Ichiyama T, Kimura H, Shibata M, Ishiwada N, Kuroki H, Furukawa S, Morishima T: Detection of influenza virus RNA by reverse transcription-PCR and proinflammatory cytokines in influenza-virus-associated encephalopathy. J Med Virol 1999, 58: 420\u2013425. 10.1002\/(SICI)1096-9071(199908)58:4<420::AID-JMV16>3.0.CO;2-T","journal-title":"J Med Virol"},{"key":"24_CR24","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1111\/j.1748-1716.1963.tb02652.x","volume":"58","author":"C Crone","year":"1963","unstructured":"Crone C: The permeability of capillaries in various organs as determined by use of the \u2018Indicator Diffusion\u2019 method. Acta Physiol Scand 1963, 58: 292\u2013305. 10.1111\/j.1748-1716.1963.tb02652.x","journal-title":"Acta Physiol Scand"},{"key":"24_CR25","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1152\/ajplegacy.1959.197.6.1205","volume":"197","author":"EM Renkin","year":"1959","unstructured":"Renkin EM: Transport of potassium-42 from blood to tissue in isolated mammalian skeletal muscles. Am J Physiol 1959, 197: 1205\u20131210.","journal-title":"Am J Physiol"},{"key":"24_CR26","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/S0006-8993(09)90022-1","volume":"658","author":"T Yamada","year":"1994","unstructured":"Yamada T, Hosokawa M, Satoh T, Moroo I, Takahashi M, Akatsu H, Yamamoto T: Immunohistochemistry with an antibody to human liver carboxylesterase in human brain tissues. Brain Res 1994, 658: 163\u2013167. 10.1016\/S0006-8993(09)90022-1","journal-title":"Brain Res"},{"key":"24_CR27","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.ejphar.2009.11.020","volume":"628","author":"L Lindemann","year":"2010","unstructured":"Lindemann L, Jacobsen H, Schuhbauer D, Knoflach F, Gatti S, Wettstein JG, Loetscher H, Chu T, Ebeling M, Paulson JC, Prinssen E, Brockhaus M: In vitro pharmacological selectivity profile of oseltamivir prodrug (Tamiflu) and active metabolite. Eur J Pharmacol 2010, 628: 6\u201310. 10.1016\/j.ejphar.2009.11.020","journal-title":"Eur J Pharmacol"},{"key":"24_CR28","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1254\/jphs.SC0070467","volume":"106","author":"A Usami","year":"2008","unstructured":"Usami A, Sasaki T, Satoh N, Akiba T, Yokoshima S, Fukuyama T, Yamatsugu K, Kanai M, Shibasaki M, Matsuki N, Ikegaya Y: Oseltamivir enhances hippocampal network synchronization. J Pharmacol Sci 2008, 106: 659\u2013662. 10.1254\/jphs.SC0070467","journal-title":"J Pharmacol Sci"}],"container-title":["EJNMMI Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13550-014-0024-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13550-014-0024-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13550-014-0024-8","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13550-014-0024-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,2]],"date-time":"2021-09-02T04:40:06Z","timestamp":1630557606000},"score":1,"resource":{"primary":{"URL":"https:\/\/ejnmmires.springeropen.com\/articles\/10.1186\/s13550-014-0024-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,7,2]]},"references-count":28,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2014,12]]}},"alternative-id":["24"],"URL":"https:\/\/doi.org\/10.1186\/s13550-014-0024-8","relation":{},"ISSN":["2191-219X"],"issn-type":[{"value":"2191-219X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,7,2]]},"assertion":[{"value":"27 December 2013","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 April 2014","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 July 2014","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"24"}}