Leishmaniasis, een verwaarloosde tropische ziekte
Wereldwijd is het leven van 1 op 6 mensen een nachtmerrie omdat ze lijden aan een ’Neglected Tropical Disease’ (NTD). Het betreft hier allerlei parasieten zoals wormen van de huid, darmen of lymfevaten, maar ook eencellige organismen zoals bacteriën. NTD’s zijn vaak eenvoudig op te lossen met geneesmiddelen of hygiënemaatregelen. Deze oplossingen dringen echter niet door tot bij de armste mensen in afgelegen gebieden of krottenwijken. Daarom spreekt men van ‘neglected’. Bovendien heeft deze groep mensen zeer weinig politieke invloed. Hiernaast spitsen de media zich vooral toe op HIV/AIDS, tuberculose en malaria. Op zich is die aandacht een goede zaak, maar omdat NTD’s naar de achtergrond verschoven worden, is het bijzonder moeilijk om fondsen te krijgen voor grootschalige bestrijdingsplannen of wetenschappelijk onderzoek.
Viscerale leishmaniasis is een van deze NTD’s. De ziekte wordt veroorzaakt door een eencellige parasiet, Leishmania, die overgedragen wordt van mens naar mens via een zandvlieg, een soort mug. De zandvlieg injecteert de parasiet in de bloedsomloop van de mens en vanaf hier begeeft hij zich naar de milt, het beenmerg en de lever. Zonder behandeling zal de ziekte bijna in alle gevallen resulteren in een dodelijke afloop.
Help, de parasiet verdraagt steeds beter onze geneesmiddelen!
Er bestaan 4 geneesmiddelen tegen leishmaniasis: Antimonialen, miltefosine, amfotericine B en paromomycine. Antimonialen werden bijna 100 jaar gebruikt om leishmaniasis te genezen. Over de jaren heen is de parasiet er echter in bepaalde gebieden in geslaagd om dit geneesmiddel beter en beter te verdragen. Hierdoor moesten de artsen telkens de dosis van het geneesmiddel verhogen om het toch nog te laten aanslaan. Op een bepaald moment was de dosis verhogen echter niet meer mogelijk, want dan werd het geneesmiddel ook toxisch voor de patiënt zelf. In sommige regio’s zoals Bihar in Nepal, kan men daarom antimonialen niet meer gebruiken.
Miltefosine is het enig oraal in te nemen geneesmiddel tegen leishmaniasis. Voor de andere moet de patiënt enkele weken in het ziekenhuis blijven voor de toediening. Helaas hervalt op sommige plaatsen reeds 30 procent van de patiënten die behandeld werden met miltefosine. Vroeger was dit slechts 5 procent.
Het is dus duidelijk dat als we Leishmania genoeg tijd geven, hij zich zodanig kan aanpassen dat onze geneesmiddelen niet meer werken. Voorlopig kunnen we nog rekenen op de goede werking van amfotericine B en paromomycine, maar het is belangrijk om de parasiet steeds een stap voor te blijven. Daarom is het essentieel om te begrijpen hoe deze geneesmiddelen juist werken, en hoe de parasiet hiertegen resistent kan worden. Helaas is van beide nog maar zeer weinig geweten. Het was dan ook het doel van mijn scriptie om aanknopingspunten te vinden voor toekomstig onderzoek naar geneesmiddelenwerking- en resistentie.
Het ontrafelen van geneesmiddelenwerking- en resistentie
Waar moet je beginnen met je onderzoek als je nauwelijks iets weet over hoe de geneesmiddelen werken? Dat is geen evidente vraag en voor mij werd het een studie op zich.
Er bestond nog geen Leishmania-stam die al resistent was tegen amfotericine B en paromomycine. Toch vonden we dat het interessant was om deze ook te bestuderen om voorbereid te zijn op de toekomst. Daarom werden in het labo stammen gemaakt die resistent zijn tegen deze geneesmiddelen. Dit is heel eenvoudig; men voert gewoon stelselmatig, gedurende een tiental weken, de concentratie van het geneesmiddel waaraan de parasiet wordt blootgesteld op. Op die manier krijgt hij de kans om het geneesmiddel steeds beter en beter te verdragen. Het was dan aan mij om te bestuderen hoe hij hier juist in slaagde.
Om die vraag op te lossen gebruikte ik een massaspectrometer. Dit is een toestel dat in staat is om honderden moleculen tegelijk te onderscheiden aan de hand van hun massa. Daarbij kan er niet bepaald worden hoeveel er precies van een bepaalde molecule in een specifieke parasietstam aanwezig was. Er kon echter wél worden vastgesteld in welke parasietstam er meer of minder molecule was ten opzichte van een niet-resistente stam.
Op die manier konden verscheidene aanknopingspunten gevonden worden voor geneesmiddelenwerking en –resistentie.
Kunnen geneesmiddelen waarvan de werking overlapt, sneller tot resistentie leiden?
Zo ontdekte ik dat amfotericine B en antimonialen mogelijk op een gelijkaardige manier de parasiet aanvallen. Ze kunnen namelijk in de parasiet toxische zuurstofproducten vormen en hem zo vernietigen. Van nature heeft Leishmania hier echter een verdedigingsmechanisme tegen. Hij bezit verscheidene moleculen (vb. thiolen en proline), die deze zuurstofproducten kunnen neutraliseren. Die zijn echter onvoldoende om de grote hoeveelheden geneesmiddel die we toedienen, te neutraliseren. Daarom slaagt het geneesmiddel er toch in om Leishmania te doden. In de resistente parasieten waren deze moleculen echter veel sterker aanwezig, waardoor hij minder gevoelig werd voor de zuurstofproducten. Aangezien de parasiet zich op dezelfde manier verdedigt tegen deze twee geneesmiddelen, is het mogelijk geen goed idee om amfotericine B te gebruiken in gebieden waar antimoniaal-resistentie is. Het zou immers kunnen dat zo resistentie tegen amfotericine B veel sneller kan ontstaan.
Miltefosine is een geneesmiddel dat inwerkt op de membraan, een dun vlies dat de parasiet omgeeft. Resistente parasieten bleken de samenstelling van deze membraan te veranderen om dit tegen te werken. Het is nog niet duidelijk waarom dit resistentie veroorzaakt, maar het is alvast een goed aanknopingspunt voor verdere studies.
Ook in paromomycine-resistente parasieten werden wijzigingen in de membraan gedetecteerd. Paromomycine zelf heeft wel geen werking op de membraan, maar het wordt wel via de membraan opgenomen. Misschien kan de parasiet dus door de wijzigingen deze opname verminderen.
De toekomst
Deze studie heeft een goede basis gelegd voor onderzoek naar geneesmiddelenwerking en -resistentie. Dit is van groot belang om nieuwe geneesmiddelen te kunnen ontwikkelen. De onderzoekers tasten zo immers niet volledig in het duister. We moeten enkel zien dat we deze geneesmiddelen sneller kunnen ontwikkelen dan dat Leishmania resistent kan worden. Het is als het ware een nooit eindigende wapenwedloop tussen de onderzoekers en de parasiet.
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Handleidingen technische materiaal
1. Thermo Scientific. Orbitrap Technology – Principle of Operation. Beschikbaar op:http://planetorbitrap.com/pdf/88415_PO30208E_12_09.pdf.
2. Thermo Scientific. Datasheet Exactive. Beschikbaar op:http://www.thermoscientific.com/ecomm/servlet/techresource?storeId=1115….
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Websites
Biovenn tool. Beschikbaar op: http://www.cmbi.ru.nl/cdd/biovenn/
Chemspider. Beschikbaar op: http://www.chemspider.com.
Lipidmaps database. Beschikbaar op: http://www.lipidmaps.org/