Background
Helminthiasis and resistance to commercial anthelmintic compounds are major causes of economic losses for livestock producers, resulting in an urgent need for new drugs and reliable in vitro screening tests capable of detecting potentially active products. Considering this, a series of novel benzimidazole derivatives (5-methylbenzimidazole 1,2-disubstituted, 5-carboxybenzimidazole, 5-methylbenzimidazole 2-one) was screened on exsheathed L3 (xL3) and on the adult stage of Haemonchus contortus (Kirby anthelmintic-susceptible McMaster isolate).
Methods
This work presents the set-up of an automated motility assay on the xL3 stage of H. contortus using an infrared tracking device (WMicrotracker One) together with a larval development test (xL3 to L4) and a motility assay on the adult stage of H. contortus. A comparative study of the sensitivity of these in vitro assays using commercial anthelmintics with different mechanisms of action was carried out, also evaluating anthelmintic activity of a series of novel benzimidazole derivatives.
Results
The automated xL3 assay had the great advantage of being able to analyze many compounds simultaneously, but it showed the limitation of having lower sensitivity, requiring higher concentrations of the commercial anthelmintics tested compared to those needed for the adult motility or development assays. Although none of the novel 1,2,5-tri-substituted benzimidazole derivatives could significantly decrease the motility of xL3s, one of them (1e) significantly affected the development of xL3s to L4, and five new compounds (1b, 1d, 1e, 2a and 2c) reduced the motility of H. contortus adult stage.
Conclusions
The analysis of the results strongly suggests that the in vitro xL3 to L4 development test, particularly for the L4 stage, could be closer to the pharmacological sensitivity of the adult stage of H. contortus (target of interest) for commercial anthelmintic selected, with different mechanisms of action, and for the series of benzimidazole derivatives assayed. Therefore, an automated motility assay on L4 using the infrared tracking device is being set up. Further studies will be conducted to evaluate the in vivo anthelmintic activity of the most active novel benzimidazole derivatives.
Graphical Abstract
Triamcinolone acetonide (TA) is a powerful anti-inflammatory drug used in the treatment of inflammatory ocular disorders; however, its poor aqueous solubility and ocular anatomical barriers hinder optimal treatment. The aim of this work was to obtain triamcinolone acetonide nanocrystals (TA-NC) to improve ocular corticosteroid therapy. Self-dispersible TA-NC were prepared by the bead milling technique followed by spray-drying, exhaustively characterized and then evaluated in vivo in an ocular model of endotoxin-induced uveitis (EIU). Self-dispersible TA-NC presented an average particle size of 257 ± 30 nm, a narrow size distribution and a zeta potential of −25 ± 3 mV, which remained unchanged for 120 days under storage conditions at 25 °C. In addition, SEM studies of the TA-NC showed uniform and spherical morphology, and FTIR and XRDP analyses indicated no apparent chemical and crystallinity changes. The subconjunctival administration of TA-NC in albino male white rabbits showed no clinical signs of ocular damage. In vivo studies proved that treatment with self-dispersible TA-NC alleviated the inflammatory response in the anterior chamber and iris in EUI rabbit eyes. Dispersible TA-NC are a promising approach to obtaining a novel nanometric TA formulation for ocular disorders.
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