{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T09:40:46Z","timestamp":1767174046609,"version":"build-2238731810"},"update-to":[{"DOI":"10.12688\/f1000research.128074.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,2,20]],"date-time":"2023-02-20T00:00:00Z","timestamp":1676851200000}}],"reference-count":59,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2023,2,20]],"date-time":"2023-02-20T00:00:00Z","timestamp":1676851200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns4:p>\n                    <ns4:bold>Background:<\/ns4:bold>\n                    Olanzapine is used to treat schizophrenia and bipolar disorder in women of childbearing age. Continuation of psychotropic medications throughout pregnancy and lactation is often required as cessation could be dangerous for both mother and child. However, there is a lack of information on the transfer of these drugs into the developing brain.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Methods:<\/ns4:bold>\n                    Sprague Dawley rats at three developmental ages: embryonic day E19, postnatal day P4 and non-pregnant adult females were administered unlabelled or radiolabelled (\n                    <ns4:sup>3<\/ns4:sup>\n                    H) olanzapine (0.15 mg\/kg) either as monotherapy or in combination with each of seven other common medications. Similar injections were administered to pregnant E19 females to investigate placental transfer. Olanzapine in plasma, cerebrospinal fluid (CSF) and brain was measured by liquid scintillation counting after a single dose (acute) or following 5 days of treatment (prolonged).\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Results:<\/ns4:bold>\n                    Olanzapine entry into brain and CSF was not age-dependent. Prolonged olanzapine treatment reduced placental transfer from 53% to 46% (p&lt;0.05). Co-administration of digoxin or lamotrigine with olanzapine increased its entry into the fetal brain, whereas paracetamol decreased its entry into the CSF. Placental transfer of olanzapine was increased by co-treatment with cimetidine and digoxin, whereas co-treatment with lamotrigine, paracetamol or valproate led to a substantial decrease. Repeated co-treatment of digoxin and olanzapine increased olanzapine transfer into the brain and CSF, but not across the placenta. Overall entry of olanzapine from maternally administered drugs into the fetal brain was higher after combination therapy with cimetidine and digoxin.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Conclusions:<\/ns4:bold>\n                    Co-administration of olanzapine with some commonly used drugs affected its entry into the fetus and its developing brain to a greater extent than in adults. It appears that protection of the fetal brain for these drugs primarily comes from the placenta rather than from the fetal brain barriers. Results suggest that drug combinations should be used with caution particularly during pregnancy.\n                  <\/ns4:p>","DOI":"10.12688\/f1000research.128074.2","type":"journal-article","created":{"date-parts":[[2023,2,20]],"date-time":"2023-02-20T11:20:23Z","timestamp":1676892023000},"page":"1417","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Entry of the antipsychotic drug, olanzapine, into the developing rat brain in mono- and combination therapies"],"prefix":"10.12688","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1060-3668","authenticated-orcid":false,"given":"Yifan","family":"Huang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fiona","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Habgood","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuai","family":"Nie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katarzyna","family":"Dziegielewska","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norman","family":"Saunders","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2560","published-online":{"date-parts":[[2023,2,20]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"508-536","DOI":"10.1212\/CON.0000000000000715","article-title":"Update on Antiepileptic Drugs 2019: CONTIN.","volume":"25","author":"B Abou-Khalil","year":"2019","journal-title":"Lifelong Learn. 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We have added a brief new paragraph&nbsp; to the introduction which emphasizes the distinction between entry of drugs across the cerebral blood vessels and via the choroid plexus and CSF. We would therefore prefer to retain choroid plexus as a key word. &quot;minutes has been corrected to &quot;min&quot; in the Methods section. It is an interesting suggestion that we should display the plasma and CSF data in Figure 2A in separate graphs. However, Figure 2A shows the time course of drug levels following administration and it is informative to be able to directly compare plasma levels that are initially high (as would be expected) with CSF levels in the same animals that are much lower. It also allows direct comparison of the fall in CSF levels which appears slower than the steep fall in plasma levels over time. This is a point being made in the section \u201cTime-course of olanzapine entry into the brain and CSF\u201d&nbsp; which references this figure.&nbsp; We would therefore prefer to retain the figure in its present form.","URL":"https:\/\/f1000research.com\/articles\/11-1417\/v2#referee-comment-9339","order":1,"name":"referee-comment-9339","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.140632.r162762, Udo Schumacher, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 13 Feb 2023, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/11-1417\/v1#referee-response-162762","order":2,"name":"referee-response-162762","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Norman Saunders<\/b>; \n<i>Posted: 14 Feb 2023<\/i>; On behalf of my co-authors I would like to thank Dr Schumacher for his kind comments about our manuscript. He makes the interesting suggestion that we should include a mention of efflux\/influx transporters in the Introduction section and not be introduced to the transport problem in the results section. Maybe even a table showing the interaction of the drugs with specific transporters\/pumps may be helpful. This is a complex and poorly understood area of research in the developing brain. When we were drafting the manuscript we considered including such a summary in the Introduction but decided that it would be clearer to readers if in the Introduction we focused on the problem being studied and left possible explanation for findings to the Discussion.","URL":"https:\/\/f1000research.com\/articles\/11-1417\/v2#referee-comment-9340","order":3,"name":"referee-comment-9340","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"The author(s) declared that no grants were involved in supporting this work","order":4,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}