Abstract
Human African trypanosomiasis (HAT or sleeping sickness) is caused by the parasite Trypanosoma brucei sspp. The disease has two stages, a haemolymphatic stage after the bite of an infected tsetse fly, followed by a central nervous system stage where the parasite penetrates the brain, causing death if untreated. Treatment is stage-specific, due to the blood-brain barrier, with less toxic drugs such as pentamidine used to treat stage 1. The objective of our research programme was to develop an intravenous formulation of pentamidine which increases CNS exposure by some 10-100 fold, leading to efficacy against a model of stage 2 HAT. This target candidate profile is in line with drugs for neglected diseases inititative recommendations. To do this, we evaluated the physicochemical and structural characteristics of formulations of pentamidine with Pluronic micelles (triblock-copolymers of polyethylene-oxide and polypropylene oxide), selected candidates for efficacy and toxicity evaluation in vitro, quantified pentamidine CNS delivery of a sub-set of formulations in vitro and in vivo, and progressed one pentamidine-Pluronic formulation for further evaluation using an in vivo single dose brain penetration study. Screening pentamidine against 40 CNS targets did not reveal any major neurotoxicity concerns, however, pentamidine had a high affinity for the imidazoline2 receptor. The reduction in insulin secretion in MIN6 β-cells by pentamidine may be secondary to pentamidine-mediated activation of β-cell imidazoline receptors and impairment of cell viability. Pluronic F68 (0.01%w/v)-pentamidine formulation had a similar inhibitory effect on insulin secretion as pentamidine alone and an additive trypanocidal effect in vitro. However, all Pluronics tested (P85, P105 and F68) did not significantly enhance brain exposure of pentamidine. These results are relevant to further developing block-copolymers as nanocarriers, improving BBB drug penetration and understanding the side effects of pentamidine.
Highlights
Human African trypanosomiasis (HAT or sleeping sickness) is a potentially fatal disease caused by the parasite Trypanosoma brucei sspp
Sleeping sickness or human African Trypanosomiasis (HAT) is a disease caused by a parasite, which is transferred to humans by the bite of an infected tsetse fly
Pluronic-pentamidine formulations were identified that harboured trypanocidal activity and did not increase safety concerns compared to unformulated pentamidine
Summary
Human African trypanosomiasis (HAT or sleeping sickness) is a potentially fatal disease caused by the parasite Trypanosoma brucei sspp. The disease has two stages–a haemolymphatic stage after the bite of an infected tsetse fly, followed by a central nervous system (CNS) stage when the parasite penetrates the brain, causing death if left untreated. The blood-brain barrier (BBB) makes the CNS stage difficult to treat because it prevents 99% of all known compounds from entering the brain, including most anti-HAT drugs [4,5,6,7] Those that do enter the brain are toxic compounds, can have serious side effects, are complex to administer and/or are expensive. The objective of our research programme was to develop an intravenous formulation of pentamidine which increases CNS exposure by some 10–100 fold, leading to efficacy against a model of stage 2 HAT This target candidate profile is in line with drugs for neglected diseases inititative recommendations
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