| The distribution of nifurtimox across the healthy and trypanosome-infected murine blood-brain and blood-cerebrospinal fluid barriers. | |
| | |
MedLine Citation:
|
PMID: 21057057 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Nifurtimox, an antiparasitic drug, is used to treat American trypanosomiasis (Chagas disease) and has shown promise in treating central nervous system (CNS)-stage human African trypanosomiasis (HAT; sleeping sickness). In combination with other antiparasitic drugs, the efficacy of nifurtimox against HAT improves, although why this happens is unclear. Studying how nifurtimox crosses the blood-brain barrier (BBB) and reaches the CNS may clarify this issue and is the focus of this study. To study the interaction of nifurtimox with the blood-CNS interfaces, we used the in situ brain/choroid plexus perfusion technique in healthy and trypanosome-infected mice and the isolated incubated choroid plexus. Results revealed that nifurtimox could cross the healthy and infected blood-brain and blood-cerebrospinal fluid (CSF) barriers (K(in) brain parenchyma was 50.8 ± 9.0 μl · min(-1) · g(-1)). In fact, the loss of barrier integrity associated with trypanosome infection failed to change the distribution of [(3)H]nifurtimox to any significant extent, suggesting there is not an effective paracellular barrier for [(3)H]nifurtimox entry into the CNS. Our studies also indicate that [(3)H]nifurtimox is not a substrate for P-glycoprotein, an efflux transporter expressed on the luminal membrane of the BBB. However, there was evidence of [(3)H]nifurtimox interaction with transporters at both the blood-brain and blood-CSF barriers as demonstrated by cross-competition studies with the other antitrypanosomal agents, eflornithine, suramin, melarsoprol, and pentamidine. Consequently, CNS efficacy may be improved with nifurtimox-pentamidine combinations, but over time may be reduced when nifurtimox is combined with eflornithine, suramin, or melarsoprol. |
| | |
Authors:
|
Sinthujah Jeganathan; Lisa Sanderson; Murat Dogruel; Jean Rodgers; Simon Croft; Sarah A Thomas |
Related Documents
:
|
8997357 - Ontogeny of blood-brain barrier function in ovine fetuses, lambs, and adults. 16717327 - Morphine-6-glucuronide: morphine's successor for postoperative pain relief? 307777 - Ventricular opacification after intravascular injections of contrast material. 22447317 - Changes in carotid blood flow following unilateral perinatal arterial ischemic stroke. 7884497 - Measurement of regional pulmonary blood flow with pet. 8853077 - Single injection thermodilution. a flow-corrected method. |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-11-05 |
Journal Detail:
|
Title: The Journal of pharmacology and experimental therapeutics Volume: 336 ISSN: 1521-0103 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2011 Feb |
Date Detail:
|
Created Date: 2011-01-19 Completed Date: 2011-03-03 Revised Date: 2011-08-03 |
Medline Journal Info:
|
Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
|
Languages: eng Pagination: 506-15 Citation Subset: IM |
Affiliation:
|
Pharmaceutical Sciences Research Division, King’s College London, London, United Kingdom. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals Blood-Brain Barrier* Choroid Plexus / metabolism* Chromatography, High Pressure Liquid Male Mice Mice, Inbred BALB C Nifurtimox / pharmacokinetics* P-Glycoprotein / physiology Protein Binding Sucrose / pharmacokinetics Trypanocidal Agents / pharmacokinetics* Trypanosoma brucei brucei* Trypanosomiasis, African / drug therapy*, metabolism |
| Grant Support | |
ID/Acronym/Agency:
|
073542//Wellcome Trust; 073542//Wellcome Trust; 080268//Wellcome Trust; 080268//Wellcome Trust |
| Chemical | |
Reg. No./Substance:
|
0/P-Glycoprotein; 0/Trypanocidal Agents; 23256-30-6/Nifurtimox; 57-50-1/Sucrose |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Spt10 and Spt21 are required for transcriptional silencing in Saccharomyces cerevisiae.
Next Document: Successful treatment of acute lung injury with pitavastatin in septic mice: potential role of glucoc...