A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis
Identifieur interne : 002E26 ( Main/Exploration ); précédent : 002E25; suivant : 002E27A murine macrofilaricide pre-clinical screening model for onchocerciasis and lymphatic filariasis
Auteurs : Alice Halliday [Royaume-Uni] ; Ana F. Guimaraes [Royaume-Uni] ; Hayley E. Tyrer [Royaume-Uni] ; Haelly Mejane Metuge [Cameroun] ; Chounna Ndongmo Winston Patrick [Cameroun] ; Kengne-Ouafo Jonas Arnaud [Cameroun] ; Tayong Dizzle Bita Kwenti [Cameroun] ; George Forsbrook [Royaume-Uni] ; Andrew Steven [Royaume-Uni] ; Darren Cook [Royaume-Uni] ; Peter Enyong [Cameroun] ; Samuel Wanji [Cameroun] ; Mark J. Taylor [Royaume-Uni] ; Joseph D. Turner [Royaume-Uni]Source :
- Parasites & Vectors [ 1756-3305 ] ; 2014.
Descripteurs français
- KwdFr :
- MESH :
- pharmacologie : Filaricides.
- traitement médicamenteux : Filariose lymphatique, Onchocercose.
- Animaux, Brugia malayi, Femelle, Gerbillinae, Mâle, Ménotropines, Onchocerca, Souris, Souris SCID, Souris de lignée BALB C.
English descriptors
- KwdEn :
- MESH :
- chemical , pharmacology : Filaricides.
- drug therapy : Elephantiasis, Filarial, Onchocerciasis.
- Animals, Brugia malayi, Female, Gerbillinae, Male, Menotropins, Mice, Mice, Inbred BALB C, Mice, SCID, Onchocerca.
Abstract
New drugs effective against adult filariae (macrofilaricides) would accelerate the elimination of lymphatic filariasis and onchocerciasis. Anti-
The filaricides: albendazole (ABZ), diethylcarbamazine (DEC), flubendazole (FBZ), ivermectin (IVM) and the anti-
WT and SCID responded with >95% efficacy following ABZ or DEC treatments against
We have developed a ‘pan-filarial’ small animal research model that is sufficiently robust, with adequate capacity and throughput, to screen existing and future pre-clinical candidate macrofilaricides. Pilot data suggests a murine onchocercoma xenograft model is achievable.
Url:
DOI: 10.1186/s13071-014-0472-z
PubMed: 25338621
PubMed Central: 4212127
Affiliations:
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Le document en format XML
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<author><name sortKey="Kwenti, Tayong Dizzle Bita" sort="Kwenti, Tayong Dizzle Bita" uniqKey="Kwenti T" first="Tayong Dizzle Bita" last="Kwenti">Tayong Dizzle Bita Kwenti</name>
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<author><name sortKey="Steven, Andrew" sort="Steven, Andrew" uniqKey="Steven A" first="Andrew" last="Steven">Andrew Steven</name>
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<author><name sortKey="Enyong, Peter" sort="Enyong, Peter" uniqKey="Enyong P" first="Peter" last="Enyong">Peter Enyong</name>
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<author><name sortKey="Wanji, Samuel" sort="Wanji, Samuel" uniqKey="Wanji S" first="Samuel" last="Wanji">Samuel Wanji</name>
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<author><name sortKey="Taylor, Mark J" sort="Taylor, Mark J" uniqKey="Taylor M" first="Mark J" last="Taylor">Mark J. Taylor</name>
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<author><name sortKey="Turner, Joseph D" sort="Turner, Joseph D" uniqKey="Turner J" first="Joseph D" last="Turner">Joseph D. Turner</name>
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<country xml:lang="fr">Royaume-Uni</country>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term>
<term>Brugia malayi</term>
<term>Elephantiasis, Filarial (drug therapy)</term>
<term>Female</term>
<term>Filaricides (pharmacology)</term>
<term>Gerbillinae</term>
<term>Male</term>
<term>Menotropins</term>
<term>Mice</term>
<term>Mice, Inbred BALB C</term>
<term>Mice, SCID</term>
<term>Onchocerca</term>
<term>Onchocerciasis (drug therapy)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term>
<term>Brugia malayi</term>
<term>Femelle</term>
<term>Filaricides (pharmacologie)</term>
<term>Filariose lymphatique (traitement médicamenteux)</term>
<term>Gerbillinae</term>
<term>Mâle</term>
<term>Ménotropines</term>
<term>Onchocerca</term>
<term>Onchocercose (traitement médicamenteux)</term>
<term>Souris</term>
<term>Souris SCID</term>
<term>Souris de lignée BALB C</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Filaricides</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Elephantiasis, Filarial</term>
<term>Onchocerciasis</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Filaricides</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Filariose lymphatique</term>
<term>Onchocercose</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Brugia malayi</term>
<term>Female</term>
<term>Gerbillinae</term>
<term>Male</term>
<term>Menotropins</term>
<term>Mice</term>
<term>Mice, Inbred BALB C</term>
<term>Mice, SCID</term>
<term>Onchocerca</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Brugia malayi</term>
<term>Femelle</term>
<term>Gerbillinae</term>
<term>Mâle</term>
<term>Ménotropines</term>
<term>Onchocerca</term>
<term>Souris</term>
<term>Souris SCID</term>
<term>Souris de lignée BALB C</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><sec><title>Background</title>
<p>New drugs effective against adult filariae (macrofilaricides) would accelerate the elimination of lymphatic filariasis and onchocerciasis. Anti-<italic>Onchocerca</italic>
drug development is hampered by the lack of a facile model. We postulated that SCID mice could be developed as a fmacrofilaricide screening model.</p>
</sec>
<sec><title>Methods</title>
<p>The filaricides: albendazole (ABZ), diethylcarbamazine (DEC), flubendazole (FBZ), ivermectin (IVM) and the anti-<italic>Wolbachia</italic>
macrofilaricide, minocycline (MIN) were tested in <italic>Brugia malayi</italic>
(<italic>Bm</italic>
)-parasitized BALB/c SCID mice <italic>vs</italic>
vehicle control (VC). Responses were compared to BALB/c wild type (WT). <italic>Onchocerca ochengi</italic>
male worms or onchocercomata were surgically implanted into BALB/c SCID, CB.17 SCID, BALB/c WT mice or <italic>Meriones</italic>
gerbils. Survival was evaluated at 7–15 days. BALB/c SCID were tested to evaluate the responsiveness of pre-clinical macrofilaricides FBZ and rifapentine (RIFAP) against male <italic>Onchocerca.</italic>
</p>
</sec>
<sec><title>Results</title>
<p>WT and SCID responded with >95% efficacy following ABZ or DEC treatments against <italic>Bm</italic>
larvae (<italic>P < 0.0001</italic>
). IVM was partially filaricidal against <italic>Bm</italic>
larvae in WT and SCID (WT; 39.8%, <italic>P = 0.0356</italic>
and SCID; 56.7%, <italic>P = 0.026</italic>
). SCID responded similarly to WT following IVM treatment of microfilaraemias (WT; 79%, <italic>P = 0.0194.</italic>
SCID; 76%, <italic>P = 0.0473</italic>
). FBZ induced a total macrofilaricidal response against adult <italic>Bm</italic>
in WT and SCID (WT; <italic>P = 0.0067,</italic>
SCID; <italic>P = 0.0071</italic>
). MIN induced a >90% reduction in <italic>Bm Wolbachia</italic>
burdens (<italic>P < 0.0001</italic>
) and a blockade of microfilarial release (<italic>P = 0.0215</italic>
) in SCID. Male <italic>Onchocerca</italic>
survival was significantly higher in SCID vs WT mice, but not gerbils, after +15 days (60% <italic>vs</italic>
22% <italic>vs</italic>
39% <italic>P = 0.0475</italic>
). Onchocercoma implants had engrafted into host tissues, with evidence of neovascularisation, after +7 days and yielded viable macro/microfilariae <italic>ex vivo</italic>
. FBZ induced a macrofilaricidal effect in <italic>Onchocerca</italic>
male implanted SCID at +5 weeks (FBZ; 1.67% <italic>vs</italic>
VC; 43.81%, <italic>P = 0.0089</italic>
). <italic>Wolbachia</italic>
loads within male <italic>Onchocerca</italic>
were reduced by 99% in implanted SCID receiving RIFAP for +2 weeks.</p>
</sec>
<sec><title>Conclusions</title>
<p>We have developed a ‘pan-filarial’ small animal research model that is sufficiently robust, with adequate capacity and throughput, to screen existing and future pre-clinical candidate macrofilaricides. Pilot data suggests a murine onchocercoma xenograft model is achievable.</p>
</sec>
</div>
</front>
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<affiliations><list><country><li>Cameroun</li>
<li>Royaume-Uni</li>
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<name sortKey="Forsbrook, George" sort="Forsbrook, George" uniqKey="Forsbrook G" first="George" last="Forsbrook">George Forsbrook</name>
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<name sortKey="Turner, Joseph D" sort="Turner, Joseph D" uniqKey="Turner J" first="Joseph D" last="Turner">Joseph D. Turner</name>
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<name sortKey="Arnaud, Kengne Ouafo Jonas" sort="Arnaud, Kengne Ouafo Jonas" uniqKey="Arnaud K" first="Kengne-Ouafo Jonas" last="Arnaud">Kengne-Ouafo Jonas Arnaud</name>
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<name sortKey="Patrick, Chounna Ndongmo Winston" sort="Patrick, Chounna Ndongmo Winston" uniqKey="Patrick C" first="Chounna Ndongmo Winston" last="Patrick">Chounna Ndongmo Winston Patrick</name>
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