{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T15:26:10Z","timestamp":1788449170518,"version":"build-2803163510"},"reference-count":22,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2009,1,29]],"date-time":"2009-01-29T00:00:00Z","timestamp":1233187200000},"content-version":"vor","delay-in-days":1458,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2005,2]]},"abstract":"<jats:p>\n<jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>Quinacrine was reported to have a marked <jats:italic>in vitro<\/jats:italic> antiprion action in mouse neuroblastoma cells. On compassionate grounds, quinacrine was administered to Creutzfeldt\u2013Jakob disease patients, despite the absence of preclinical <jats:italic>in vivo<\/jats:italic> studies to evaluate efficacy. Quinacrine failed to provide therapeutic benefit. The aim of the study was to investigate possible pharmacokinetic and\/or pharmacodynamic explanations for the discrepancy between the proven action of quinacrine <jats:italic>in vitro<\/jats:italic> and its lack of clinical efficacy.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We conducted <jats:italic>in vitro<\/jats:italic> experiments reproducing the culture conditions in which antiprion effects had been previously observed and recalculated the EC<jats:sub>50<\/jats:sub> by determining the actual extracellular (120\u2003n<jats:sc>M<\/jats:sc>) and intracellular (6713\u2003n<jats:sc>M<\/jats:sc>) quinacrine neuroblastoma concentrations with the reported quinacrine EC<jats:sub>50<\/jats:sub> (300\u2003n<jats:sc>M<\/jats:sc>).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>A randomized clinical trial in scrapie\u2010affected ewes confirmed the absence of therapeutic benefit of quinacrine. The <jats:italic>in vivo<\/jats:italic> quinacrine exposure was evaluated in a pharmacokinetic investigation in healthy ewes. Cerebrospinal fluid concentrations (&lt;10.6 and 55\u2003n<jats:sc>M<\/jats:sc> after administration of therapeutic and toxic quinacrine doses, respectively) were much lower than the quinacrine extracellular neuroblastoma concentrations corresponding to the reported EC<jats:sub>50<\/jats:sub>. The total brain tissue concentrations (3556\u2003n<jats:sc>M<\/jats:sc>) obtained after a repeated therapeutic dosage regimen were within the range of the intracellular neuroblastoma quinacrine concentrations.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In conclusion, in order to avoid <jats:italic>in vivo<\/jats:italic> trials for which failure can be predicted, the measurement <jats:italic>in vitro<\/jats:italic> of the antiprion EC<jats:sub>50<\/jats:sub> in both intra\u2010 and extracellular biophases should be determined. It can then be established if these <jats:italic>in vitro<\/jats:italic> antiprion concentrations are achievable <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2005) <jats:bold>144<\/jats:bold>, 386\u2013393. doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0706072\">10.1038\/sj.bjp.0706072<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0706072","type":"journal-article","created":{"date-parts":[[2005,1,17]],"date-time":"2005-01-17T18:25:43Z","timestamp":1105986343000},"page":"386-393","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["A possible pharmacological explanation for quinacrine failure to treat prion diseases: pharmacokinetic investigations in a ovine model of scrapie"],"prefix":"10.1111","volume":"144","author":[{"given":"V\u00e9ronique","family":"Gayrard","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Picard\u2010Hagen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Vigui\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Laroute","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Andr\u00e9oletti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre\u2010Louis","family":"Toutain","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,1,29]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.15.8462-8469.2003"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-4347(87)80189-5"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(89)90298-X"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10336"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200241100-00001"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1023\/B:CEMN.0000018617.21378.95"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.74.10.4894-4897.2000"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0015-0282(16)46703-8"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.299.5604.191"},{"key":"e_1_2_7_11_1","first-page":"1649","article-title":"Prospects of the therapeutic approaches to Creutzfeldt\u2013Jakob disease: a clinical trial of antimalarial, quinacrine","volume":"60","author":"FURUKAWA H.","year":"2002","journal-title":"Nippon Rinsho"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1201\/b14095"},{"key":"e_1_2_7_13_1","first-page":"1167","volume-title":"The Pharmacological Basis of Therapeutics","author":"GOODMAN L.S.","year":"1960"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.41.9.1482"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.161274798"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.41.24589"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1159\/000076350"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0163-7258(97)00084-3"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.140.5.2422"},{"key":"e_1_2_7_20_1","first-page":"307","article-title":"The pharmacological basis for the rational use of atabrine in the treatment of malaria","volume":"81","author":"SHANNON J.A.","year":"1944","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)82340-7"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm034093h"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01117450"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1038%2Fsj.bjp.0706072","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1038%2Fsj.bjp.0706072","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1038\/sj.bjp.0706072","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,13]],"date-time":"2023-10-13T02:36:17Z","timestamp":1697164577000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1038\/sj.bjp.0706072"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2005,2]]},"references-count":22,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2005,2]]}},"alternative-id":["10.1038\/sj.bjp.0706072"],"URL":"https:\/\/doi.org\/10.1038\/sj.bjp.0706072","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2005,2]]},"assertion":[{"value":"2009-01-29","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}