The following handle holds various files of this Leiden University dissertation:
http://hdl.handle.net/1887/81579
Author: Vendel, E.
Title: Prediction of spatial-temporal brain drug distribution with a novel mathematical
model
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Het succes van medicijnen die ontwikkeld zijn om ziekten van de hersenen te ge-nezen is nog altijd beperkt. Een belangrijke reden hiervoor is het beperkte inzicht in de complexiteit van de hersenen en in hoe een medicijn zich binnen de herse-nen distribueert. Dit is erg belangrijk om de werking en de bijwerkingen van een medicijn te kunnen begrijpen. Wiskundige modellen kunnen inzicht in de distri-butie, en de daaraan gerelateerde werking, van een medicijn binnen de hersenen vooruithelpen. Een wiskundig model is in wezen een abstracte beschrijving van een bepaald fenomeen uit de werkelijkheid. Alle wiskundige modellen zijn een versim-peling van de werkelijkheid; juist door deze versimversim-peling wordt het bestudeerde fenomeen overzichtelijker en kunnen er makkelijker inzichten over bijvoorbeeld het ontstaan van een fenomeen worden verkregen. In dit proefschrift wordt stap voor stap een wiskundig model, het 3d brain model, gebouwd om de distributie van een medicijn naar en binnen de hersenen over tijd en ruimte te bestuderen.
Achtergrond
ob-stakels wordt diffusie binnen de hersen-ECF gehinderd en is de effectieve diffusie van een medicijn binnen de hersen-ECF lager dan de vrije diffusie van ditzelfde medicijn in water. De impact van de bulkstroming van de hersen-ECF op medi-cijntransport binnen de extracellulaire hersenvloeistof staat onder discussie, maar er is bewijs dat bulkstroming belangrijk is voor de verspreiding van een medicijn binnen de hersenen. De binding van een medicijn aan cellulaire componenten kan specifiek maar ook niet specifiek zijn, en kan zowel intra- als extracellulair plaats-vinden. Specifieke bindingsplaatsen zijn de plaatsen waar een medicijn aan bindt (op basis van de eigenschappen van het medicijn) en door die binding een gewenste werking teweegbrengt. Niet-specifieke bindingsplaatsen zijn de plaatsen waar een medicijn niet voor ontworpen is om aan te binden en daar, door binding, helemaal geen, of een ongewenste werking teweegbrengt. De specifieke binding is in de regel sterker dan de niet-specifieke binding.
Het BHB-transport en de verspreiding van het medicijn in de hersenen verschilt per medicijn en individu en wordt bovendien beïnvloed door factoren zoals voeding, leeftijd en ziekte. Bovendien kunnen de processen verschillend zijn tussen plaatsen binnen de hersenen, door bijvoorbeeld variaties in eigenschappen binnen de her-senen of door lokale ziekteprocessen. Omdat een medicijn alleen werkt wanneer het specifiek gebonden is aan haar doelwit, de ‘target’, bepaalt het lokale medi-cijntransport over zowel de BHB als binnen de hersenen uiteindelijk het effect van het medicijn. Er is dus begrip nodig van de factoren die de lokale concentratie-tijdsprofielen van medicijnen in de hersenen bepalen en daarmee uiteindelijk de effecten van een medicijn beïnvloeden. Wiskundige modellen kunnen helpen bij dit begrip.
In het tweede deel van hoofdstuk 2 wordt een overzicht gegeven van modellen die veranderingen in de concentratie-tijdsprofielen van medicijnen in de hersenen beschrijven. De reeds bestaande modellen richten zich meestal slechts op één pro-ces. Zo zijn er modellen die medicijntransport over de BHB beschrijven en is er veel onderzoek verricht om medicijntransport door de hersen-ECF (via diffusie en bulkstroming) te beschrijven. In ‘farmacokinetische modellen’ wordt vaak het transport van een medicijn tussen verschillende delen binnen en rondom de herse-nen beschreven, zoals het bloed, de extracellulaire hersenvloeistof, de cerebrospina-le hersenvloeistof en de celcerebrospina-len, met behulp van gewone differentiaalvergelijkingen. Echter wordt hierbij de distributie van medicijnen binnen deze delen niet in acht genomen. Er zijn daarom modellen nodig die niet alleen het transport tussen de onderdelen van de hersenen bestuderen, maar ook het ruimtelijk transport
bin-nen deze delen beschrijven. Deze modellen zijn schaars. Er is dus behoefte aan
