Short-course, oral flubendazole does not mediate significant efficacy against Onchocerca adult male worms or Brugia microfilariae in murine infection models.
The Onchocerca ochengi adult implant and Brugia malayi microfilariemic Severe-Combined Immunodeficient (SCID) mouse models are validated screens to measure macrofilaricidal and microfilaricidal activities of candidate onchocerciasis drugs. The purpose of this study was to assess whether 5 daily sub-...
Published in: | PLOS Neglected Tropical Diseases |
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ftdoajarticles:oai:doaj.org/article:fe1c618c58354c30b115c91c359195be 2023-05-15T15:16:20+02:00 Short-course, oral flubendazole does not mediate significant efficacy against Onchocerca adult male worms or Brugia microfilariae in murine infection models. Hanna T Sjoberg Nicolas Pionnier Ghaith Aljayyoussi Haelly M Metuge Abdel J Njouendou Valerine C Chunda Fanny F Fombad Dizzle B Tayong Narcisse V T Gandjui Desmond N Akumtoh Patrick W N Chounna Bertrand L Ndzeshang Sophie Lachaud Fetene Tekle Ludo Quirynen Marc Engelen Benny Baeten Andrew Steven Stephen A Ward Mark J Taylor Samuel Wanji Joseph D Turner 2019-01-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0006356 https://doaj.org/article/fe1c618c58354c30b115c91c359195be EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0006356 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0006356 https://doaj.org/article/fe1c618c58354c30b115c91c359195be PLoS Neglected Tropical Diseases, Vol 13, Iss 1, p e0006356 (2019) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2019 ftdoajarticles https://doi.org/10.1371/journal.pntd.0006356 2022-12-31T11:01:42Z The Onchocerca ochengi adult implant and Brugia malayi microfilariemic Severe-Combined Immunodeficient (SCID) mouse models are validated screens to measure macrofilaricidal and microfilaricidal activities of candidate onchocerciasis drugs. The purpose of this study was to assess whether 5 daily sub-cutaneous (s.c.) injections of standard flubendazole (FBZ) suspension (10mg/kg), a single s.c. injection (10mg/kg) or 5 daily repeated oral doses of FBZ amorphous solid dispersion (ASD) formulation (0.2, 1.5 or 15mg/kg) mediated macrofilaricidal efficacy against O. ochengi male worms implanted into SCID mice. The direct microfilaricidal activity against circulating B. malayi microfilariae of single dose FBZ ASD formulation (2 or 40 mg/kg) was also evaluated and compared against the standard microfilaricide, ivermectin (IVM). Systemic exposures of FBZ/FBZ metabolites achieved following dosing were measured by pharmacokinetic (PK) bioanalysis. At necropsy, five weeks following start of FBZ SC injections, there were significant reductions in burdens of motile O. ochengi worms following multiple injections (93%) or single injection (82%). Further, significant proportions of mice dosed following multiple injections (5/6; 83%) or single injection (6/10; 60%) were infection negative (drug-cured). In comparison, no significant reduction in recovery of motile adult O. ochengi adult worms was obtained in any multiple-oral dosage group. Single oral-dosed FBZ did not mediate any significant microfilaricidal activity against circulating B. malayi mf at 2 or 7 days compared with >80% efficacy of single dose IVM. In conclusion, multiple oral FBZ formulation doses, whilst achieving substantial bioavailability, do not emulate the efficacy delivered by the parenteral route in vivo against adult O. ochengi. PK analysis determined FBZ efficacy was related to sustained systemic drug levels rather than achievable Cmax. PK modelling predicted that oral FBZ would have to be given at low dose for up to 5 weeks in the mouse model to achieve ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 13 1 e0006356 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Hanna T Sjoberg Nicolas Pionnier Ghaith Aljayyoussi Haelly M Metuge Abdel J Njouendou Valerine C Chunda Fanny F Fombad Dizzle B Tayong Narcisse V T Gandjui Desmond N Akumtoh Patrick W N Chounna Bertrand L Ndzeshang Sophie Lachaud Fetene Tekle Ludo Quirynen Marc Engelen Benny Baeten Andrew Steven Stephen A Ward Mark J Taylor Samuel Wanji Joseph D Turner Short-course, oral flubendazole does not mediate significant efficacy against Onchocerca adult male worms or Brugia microfilariae in murine infection models. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
The Onchocerca ochengi adult implant and Brugia malayi microfilariemic Severe-Combined Immunodeficient (SCID) mouse models are validated screens to measure macrofilaricidal and microfilaricidal activities of candidate onchocerciasis drugs. The purpose of this study was to assess whether 5 daily sub-cutaneous (s.c.) injections of standard flubendazole (FBZ) suspension (10mg/kg), a single s.c. injection (10mg/kg) or 5 daily repeated oral doses of FBZ amorphous solid dispersion (ASD) formulation (0.2, 1.5 or 15mg/kg) mediated macrofilaricidal efficacy against O. ochengi male worms implanted into SCID mice. The direct microfilaricidal activity against circulating B. malayi microfilariae of single dose FBZ ASD formulation (2 or 40 mg/kg) was also evaluated and compared against the standard microfilaricide, ivermectin (IVM). Systemic exposures of FBZ/FBZ metabolites achieved following dosing were measured by pharmacokinetic (PK) bioanalysis. At necropsy, five weeks following start of FBZ SC injections, there were significant reductions in burdens of motile O. ochengi worms following multiple injections (93%) or single injection (82%). Further, significant proportions of mice dosed following multiple injections (5/6; 83%) or single injection (6/10; 60%) were infection negative (drug-cured). In comparison, no significant reduction in recovery of motile adult O. ochengi adult worms was obtained in any multiple-oral dosage group. Single oral-dosed FBZ did not mediate any significant microfilaricidal activity against circulating B. malayi mf at 2 or 7 days compared with >80% efficacy of single dose IVM. In conclusion, multiple oral FBZ formulation doses, whilst achieving substantial bioavailability, do not emulate the efficacy delivered by the parenteral route in vivo against adult O. ochengi. PK analysis determined FBZ efficacy was related to sustained systemic drug levels rather than achievable Cmax. PK modelling predicted that oral FBZ would have to be given at low dose for up to 5 weeks in the mouse model to achieve ... |
format |
Article in Journal/Newspaper |
author |
Hanna T Sjoberg Nicolas Pionnier Ghaith Aljayyoussi Haelly M Metuge Abdel J Njouendou Valerine C Chunda Fanny F Fombad Dizzle B Tayong Narcisse V T Gandjui Desmond N Akumtoh Patrick W N Chounna Bertrand L Ndzeshang Sophie Lachaud Fetene Tekle Ludo Quirynen Marc Engelen Benny Baeten Andrew Steven Stephen A Ward Mark J Taylor Samuel Wanji Joseph D Turner |
author_facet |
Hanna T Sjoberg Nicolas Pionnier Ghaith Aljayyoussi Haelly M Metuge Abdel J Njouendou Valerine C Chunda Fanny F Fombad Dizzle B Tayong Narcisse V T Gandjui Desmond N Akumtoh Patrick W N Chounna Bertrand L Ndzeshang Sophie Lachaud Fetene Tekle Ludo Quirynen Marc Engelen Benny Baeten Andrew Steven Stephen A Ward Mark J Taylor Samuel Wanji Joseph D Turner |
author_sort |
Hanna T Sjoberg |
title |
Short-course, oral flubendazole does not mediate significant efficacy against Onchocerca adult male worms or Brugia microfilariae in murine infection models. |
title_short |
Short-course, oral flubendazole does not mediate significant efficacy against Onchocerca adult male worms or Brugia microfilariae in murine infection models. |
title_full |
Short-course, oral flubendazole does not mediate significant efficacy against Onchocerca adult male worms or Brugia microfilariae in murine infection models. |
title_fullStr |
Short-course, oral flubendazole does not mediate significant efficacy against Onchocerca adult male worms or Brugia microfilariae in murine infection models. |
title_full_unstemmed |
Short-course, oral flubendazole does not mediate significant efficacy against Onchocerca adult male worms or Brugia microfilariae in murine infection models. |
title_sort |
short-course, oral flubendazole does not mediate significant efficacy against onchocerca adult male worms or brugia microfilariae in murine infection models. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2019 |
url |
https://doi.org/10.1371/journal.pntd.0006356 https://doaj.org/article/fe1c618c58354c30b115c91c359195be |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 13, Iss 1, p e0006356 (2019) |
op_relation |
https://doi.org/10.1371/journal.pntd.0006356 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0006356 https://doaj.org/article/fe1c618c58354c30b115c91c359195be |
op_doi |
https://doi.org/10.1371/journal.pntd.0006356 |
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PLOS Neglected Tropical Diseases |
container_volume |
13 |
container_issue |
1 |
container_start_page |
e0006356 |
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1766346622467309568 |