16 research outputs found
The blood–brain barrier significantly limits eflornithine entry into Trypanosoma brucei brucei infected mouse brain1
Drugs to treat African trypanosomiasis are toxic, expensive and subject to parasite resistance. New drugs are urgently being sought. Although the existing drug, eflornithine, is assumed to reach the brain in high concentrations, little is known about how it crosses the healthy and infected blood–brain barrier. This information is essential for the design of drug combinations and new drugs. This study used novel combinations of animal models to address these omissions. Eflornithine crossed the healthy blood–CNS interfaces poorly, but this could be improved by co-administering suramin, but not nifurtimox, pentamidine or melarsoprol. Work using a murine model of sleeping sickness demonstrated that Trypanosoma brucei brucei crossed the blood–CNS interfaces, which remained functional, early in the course of infection. Concentrations of brain parasites increased during the infection and this resulted in detectable blood–brain barrier, but not choroid plexus, dysfunction at day 28 post-infection with resultant increases in eflornithine brain delivery. Barrier integrity was never restored and the animals died at day 37.9 ± 1.2. This study indicates why an intensive treatment regimen of eflornithine is required (poor blood–brain barrier penetration) and suggests a possible remedy (combining eflornithine with suramin). The blood–brain barrier retains functionality until a late, possibly terminal stage, of trypanosoma infection
Pentamidine Movement across the Murine Blood-Brain and Blood-Cerebrospinal Fluid Barriers: Effect of Trypanosome Infection, Combination Therapy, P-Glycoprotein, and Multidrug Resistance-Associated Protein
During the first stage of human African trypanosomiasis (HAT),
Trypanosoma brucei gambiense is found mainly in the blood, and
pentamidine treatment is used. Pentamidine is predominantly ineffective once
the parasites have invaded the central nervous system (CNS). This lack of
efficacy is thought to be due to the inability of pentamidine to cross the
blood-brain barrier, although this has never been explored directly. This
study addresses this using brain perfusion in healthy mice,
P-glycoprotein-deficient mice, and in a murine model of HAT (T. brucei
brucei). The influence of additional antitrypanosomal drugs on
pentamidine delivery to the CNS also was investigated. Results revealed that
[3H]pentamidine can cross the blood-brain barrier, although a
proportion was retained by the capillary endothelium and failed to reach the
healthy or trypanosome-infected brain (up to day 21 p.i.). The CNS
distribution of pentamidine was increased in the final (possibly terminal)
stage of trypanosome infection, partly because of loss of barrier integrity
(days 28–35 p.i.) as measured by [14C]sucrose and
[3H]suramin. Furthermore, pentamidine distribution to the CNS
involved influx and efflux [via P-glycoprotein and multidrug
resistance-associated protein (MRP)] transporters and was affected by the
other antitrypanosomal agents, suramin, melarsoprol, and nifurtimox, but not
eflornithine. These interactions could contribute to side effects or lead to
the development of parasite resistance to the drugs. Thus, great care must be
taken when designing drug combinations containing pentamidine or other
diamidine analogs. However, coadministration of P-glycoprotein and/or MRP
inhibitors with pentamidine or other diamidines might provide a means of
improving efficacy against CNS stage HAT