An In Vitro/In Vivo Model to Analyze the Effects of Flubendazole Exposure on Adult Female Brugia malayi

O’Neill, Maeghan; Mansour, Abdelmoneim; DiCosty, Utami; Geary, James; Dzimianski, Michael T.; McCall, Scott; McCall, John W.; Mackenzie, Charles D.; Geary, Timothy G.

doi:10.1371/journal.pntd.0004698

Cited by 25 publications

(24 citation statements)

References 35 publications

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“…Down-regulation of genes involved in early embryo morphogenesis may explain the apparent halt of embryogenesis associated with FLBZ exposure (O'Neill et al., 2016). Short-term in vitro exposure to FLBZ followed by long-term maintenance in vivo resulted in an increase in late morula stage embryos, the stage preceding the onset of elongation.…”

Section: Discussionmentioning

confidence: 99%

“…Exposure to relatively high but pharmacologically relevant concentrations (10 μM) of FLBZ for 24 h was not lethal and worms were able to recover (O'Neill et al., 2015, O'Neill et al., 2016). These studies used histological techniques to assess tissues damage in an effort to determine a concentration range which may be lethal over this time-period.…”

Section: Discussionmentioning

confidence: 99%

“…In the current study, we used the RNAseq approach to identify significant genes and biological processes that were being affected in B. malayi when challenged with FLBZ. Analysis of GO terms highlights the influence FLBZ on filarial embryonic development, consistent with previous findings (O'Neill et al., 2015, O'Neill et al., 2016). Significantly enriched GO terms are commonly associated with RNAi phenotypes of embryo/larval lethality or impairments to overall morphogenesis for C. elegans homologues.…”

Section: Discussionmentioning

confidence: 99%

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Profiling the macrofilaricidal effects of flubendazole on adult female Brugia malayi using RNAseq

O’Neill

Ballesteros

Tritten

et al. 2016

International Journal for Parasitology: Drugs and Drug Resistan

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The use of microfilaricidal drugs for the control of onchocerciasis and lymphatic filariasis (LF) necessitates prolonged yearly dosing. Prospects for elimination or eradication of these diseases would be enhanced by the availability of a macrofilaricidal drug. Flubendazole (FLBZ), a benzimidazole anthelmintic, is an appealing candidate. FLBZ has demonstrated potent macrofilaricidal effects in a number of experimental rodent models and in one human trial. Unfortunately, FLBZ was deemed unsatisfactory for use in mass drug administration campaigns due to its limited oral bioavailability. A new formulation that enables sufficient bioavailability following oral administration could render FLBZ an effective treatment for onchocerciasis and LF. Identification of drug-derived effects is important in ascertaining a dosage regimen which is predicted to be lethal to the parasite in situ. In previous histological studies, exposure to FLBZ induced damage to tissues required for reproduction and survival at pharmacologically relevant concentrations. However, more precise and quantitative indices of drug effects are needed. This study assessed drug effects using a transcriptomic approach to confirm effects observed histologically and to identify genes which were differentially expressed in treated adult female Brugia malayi. Comparative analysis across different concentrations (1 μM and 5 μM) and durations (48 and 120 h) provided an overview of the processes which are affected by FLBZ exposure. Genes with dysregulated expression were consistent with the reproductive effects observed via histology in our previous studies. This study revealed transcriptional changes in genes involved in embryo development. Additionally, significant downregulation was observed in genes encoding cuticle components, which may reflect changes in developing embryos, the adult worm cuticle or both. These data support the hypothesis that FLBZ acts predominantly on rapidly dividing cells, and provides a basis for selecting molecular markers of drug-induced damage which may be of use in predicting efficacious FLBZ regimens.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Profiling the macrofilaricidal effects of flubendazole on adult female Brugia malayi using RNAseq

O’Neill

Ballesteros

Tritten

et al. 2016

International Journal for Parasitology: Drugs and Drug Resistan

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“…Plates were incubated in a humid 5% CO 2 atmosphere at 37°C for 48 h and were observed under an inverted microscope at 2, 4, 6, 24, 30, and 48 h to count the dead worms. Parasites viability was estimated analyzing their motility and morphology, and they were classified into two categories: (0) dead; (1) alive, with normal morphology and varying degrees of motility [27]. The ABZ solution was used as the positive control and the culture medium with DMSO as the negative control.…”

Section: Dementioning

confidence: 99%

Synthesis and characterization of a new cyclodextrin derivative with improved properties to design oral dosage forms

Garcı́a

Priotti

Codina

et al. 2018

Drug Deliv. and Transl. Res.

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This work aimed to synthesize a novel β-cyclodextrin derivative, itaconyl-β-cyclodextrin to evaluate whether albendazole inclusion complexes with the new β-cyclodextrin derivative-improved albendazole dissolution efficiency and its anthelminthic activity. The new derivative was thoroughly evaluated and characterized, and an average degree of substitution of 1.4 per cyclodextrin molecule was observed. Albendazole:itaconyl-β-cyclodextrin complexes were prepared by spray drying procedures and investigated using phase solubility diagrams, dissolution efficiency, X-ray diffraction, differential scanning calorimetry, Fourier transform infrared, scanning electronic microscopy, mass spectrometry, and nuclear magnetic resonance spectroscopy. Phase solubility diagrams and mass spectrometry studies showed that the inclusion complex was formed in an equimolar ratio. Stability constant values were 602 M −1 in water, and 149 M −1 in HCl 0.1 N. Nuclear magnetic resonance experiments of the inclusion complex showed correlation signals between the aromatic and propyl protons of albendazole and the itaconyl-βcyclodextrin inner protons. The studies indicated solid structure changes of albendazole included in itaconyl-β-cyclodextrin. The maximum drug release was reached at 15 min, and the inclusion complex solubility was 88-fold higher than that of the pure drug. The in vitro anthelmintic activity assay showed that the complex was significantly more effective than pure albendazole.

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“…Different ways of assessing the state of worms in histological sections have been used. A scoring system that has been developed and used successfully for the investigation of new chemotherapeutic agents [11,12] and the type of degenerating forms seen in such studies shown…”

Section: Nematology -Concepts Diagnosis and Controlmentioning

confidence: 99%

Assessing the Viability and Degeneration of the Medically Important Filarial Nematodes

Mackenzie¹,

Behan‐Braman²,

Hauptman³

et al. 2017

Nematology - Concepts, Diagnosis and Control

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The assessment of nematodes as they generate and die is not a simple thing to do due in part to the complexity of the organism, and the fact that still relatively little is known about their physiology and internal biology. Indeed, the pathological changes in the internal organs of the worms are still only recognized in general terms. Obviously dead worms are easily recognized (when fractured, or calcified, etc.) but the lesser obvious changes can be difficult to detect and interpret. The point at which a worm can be defined as dead is not a simple matter; cessation of motility is currently the most commonly used parameter for this but it is not always a robust indicator and better indicators are needed. Various methods can be used to assess the presence, viability, and functionality of nematodes but these must be used with an understanding of the situation at hand and the specific questions being addressed. Careful use of appropriate statistics is essential given the complex nature of the target organism and the variability in the changes that can be seen within even one anatomical component of these worms. Histological assessment of the parasites present in both parasitized host tissues and isolated worms used in in vitro experiments can provide information that gives a more detailed understanding of the changes in nematodes as they degenerate and die. Understanding of the pathways nematodes follows as they degenerate naturally or under various external pressures, such as chemotherapy, remains a fascinating and potentially productive goal for investigation. Likewise, a complete understanding and definition of specific indicators that reflect parasite load, parasite viability, and damage, or reduced fecundity, will greatly help the fight against those nematode infections that currently cause significant burdens of disease in humans and animals.

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An In Vitro/In Vivo Model to Analyze the Effects of Flubendazole Exposure on Adult Female Brugia malayi

Cited by 25 publications

References 35 publications

Profiling the macrofilaricidal effects of flubendazole on adult female Brugia malayi using RNAseq

Profiling the macrofilaricidal effects of flubendazole on adult female Brugia malayi using RNAseq

Synthesis and characterization of a new cyclodextrin derivative with improved properties to design oral dosage forms

Assessing the Viability and Degeneration of the Medically Important Filarial Nematodes

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