Drug reformulation for a neglected disease. The NANOHAT project to develop a safer more effective sleeping sickness drug

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. MethodologyTo 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 evaluationin vitro, quantified pentamidine CNS delivery of a sub-set of formulationsin vitro and in vivo, and progressed one pentamidine-Pluronic formulation for further evaluation using anin vivo single dose brain penetration study. Principal FindingsScreening 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 effectin vitro. However, all Pluronics tested (P85, P105 and F68) did not significantly enhance brain exposure of pentamidine. SignificanceThese results are relevant to further develo...
Source: PLoS Neglected Tropical Diseases - Category: Tropical Medicine Authors: Source Type: research