Brugia malayi: In vitro effects of ivermectin and moxidectin on adults and microfilariae

Tompkins, Jeffrey B.; Stitt, Laurel E.; Ardelli, Bernadette F.

doi:10.1016/j.exppara.2009.12.003

Cited by 35 publications

(43 citation statements)

References 34 publications

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“…Sensitivity to IVM was potentiated when the drug was In this study, we demonstrated that B. malayi adults are sensitive to IVM as shown by the decrease in motility, the eventual paralysis and death, and by inhibition of microfilariae release in females. These results confirmed those of Tompkins et al (2010) who demonstrated that motility was significantly reduced in adult B. malayi after exposure to an IVM concentration gradient ranging from 0.15 to 5,000 μg/mL. Thus, while adults are sensitive to IVM, the sensitivity appears to be less than that observed in other nematodes (e.g., C. elegans) exposed to comparable drug concentrations, as B. malayi do not succumb to paralysis as quickly (Ardelli et al 2009).…”

Section: Discussionsupporting

confidence: 92%

“…Thus, there are no reported effects of IVM blocking feeding in B. malayi. In filarioid nematodes, reproduction is more sensitive to the effects of IVM in comparison to C. elegans (Ardelli et al 2009;Gardon et al 2002;Tompkins et al 2010). Despite having significant in vitro macrofilaridical effects, IVM appears to have no significant measurable in vivo effect on adult filarioids (Gardon et al 2002;Tompkins et al 2010).…”

Section: Introductionmentioning

confidence: 83%

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The role of Brugia malayi ATP-binding cassette (ABC) transporters in potentiating drug sensitivity

et al. 2011

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ATP binding cassette (ABC) systems are a diverse group of proteins that have been identified in every organism, from bacteria to humans. Analysis of nematode genomes indicates that the number and arrangement of ABC systems are similar to other organisms, with the majority being ABC transporters. There are few functional studies of ABC transporters in parasitic nematodes; most reports have been on their identification or use as genetic markers to monitor drug resistance. In eukaryotes, some ABC transporters function in tissue defense by actively removing drugs, thus preventing their accumulation. The overexpression of ABC transporters that function as efflux pumps, such as P-glycoprotein (PGP) and the multidrug resistance associated protein (MRP) are known to confer resistance. Drug sensitivity can be restored by administration of PGP interfering or MDR reversal agents. The objective of this study was to determine if ABC systems in filarioid nematodes function similarly to those of other organisms. The relative expression of 33 ABC systems identified in Brugia malayi was quantified following exogenous exposure to the commonly used drug ivermectin (IVM). Following exposure of adults and microfilariae to IVM, there was a significant increase in the transcriptional profiles of a number of ABC systems, mostly within the PGP and MRP subgroups. Coadministration of PGP-interfering and MDR-reversal agents with IVM potentiated sensitivity to the drug in adults and microfilariae. The results suggest that B. malayi ABC transporters function similarly to those in other organisms and are a factor in determining drug sensitivity.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 83%

The role of Brugia malayi ATP-binding cassette (ABC) transporters in potentiating drug sensitivity

et al. 2011

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“…It has been commonly observed that IVM does not affect mf motility or viability at pharmacologically relevant concentrations in culture (5,9), which is consistent with the apparent absence of GluCl expression in regions associated with somatic muscle function. Recently, it has been reported that IVM concentrations >1 μM affect mf motility (29); this may be associated with drug effects on GABA-gated chloride channels, which are secondary targets for the ML class (30). These effects may partially account for the concentration-dependence of the drug effect on secretion seen at the later time-point.…”

Section: Discussionmentioning

confidence: 99%

Ivermectin disrupts the function of the excretory-secretory apparatus in microfilariae of Brugia malayi

Moreno

Nabhan

Solomon

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

147

141

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Ivermectin (IVM) is a broad-spectrum anthelmintic used in filariasis control programs. By binding to nematode glutamate-gated chloride channels (GluCls), IVM disrupts neurotransmission processes regulated by GluCl activity. IVM treatment of filarial infections is characterized by an initial dramatic drop in the levels of circulating microfilariae, followed by long-term suppression of their production, but the drug has little direct effect on microfilariae in culture at pharmacologically relevant concentrations. We localized Brugia malayi GluCl expression solely in a muscle structure that surrounds the microfilarial excretory-secretory (ES) vesicle, which suggests that protein release from the ES vesicle is regulated by GluCl activity. Consistent with this hypothesis, exposure to IVM in vitro decreased the amount of protein released from microfilariae. To better understand the scope of IVM effects on protein release by the parasite, three different expression patterns were identified from immunolocalization assays on a representative group of five microfilarial ES products. Patterns of expression suggest that the ES apparatus is the main source of regulated ES product release from microfilariae, as it is the only compartment that appears to be under neuromuscular control. Our results show that IVM treatment of microfilariae results in a marked reduction of protein release from the ES apparatus. Under in vivo conditions, the rapid microfilarial clearance induced by IVM treatment is proposed to result from suppression of the ability of the parasite to secrete proteins that enable evasion of the host immune system. filarial nematode | macrocyclic lactone | glutamate-gated chloride channels

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“…Ivermectin was approximately 10 times more potent than moxidectin in a variety of fly species (19). Differences in toxicity between the macrocyclic lactones are less apparent in nematodes (27); however, studies of B. malayi and Caenorhabditis elegans show differences between phenotypic effects of the drugs, suggesting that different target sites exist (32,33). While moxidectin and ivermectin have similar mechanisms of action, the existence of different binding targets is further reflected by differences in ABC transporter-mediated efflux, for example (21).…”

mentioning

confidence: 98%

In Vitro Efficacy of Moxidectin versus Ivermectin against Sarcoptes scabiei

Mounsey

Walton

Innes

et al. 2017

Antimicrob Agents Chemother

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Moxidectin is under consideration for development as a treatment for human scabies. As some arthropods show decreased sensitivity to moxidectin relative to ivermectin, it was important to assess this for Sarcoptes scabiei. In vitro assays showed that the concentration of moxidectin required to kill 50% of mites was lower than that of ivermectin (0.5 M versus 1.8 M at 24 h; P Ͻ 0.0001). This finding provides further support for moxidectin as a candidate for the treatment of human scabies.

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Brugia malayi: In vitro effects of ivermectin and moxidectin on adults and microfilariae

Cited by 35 publications

References 34 publications

The role of Brugia malayi ATP-binding cassette (ABC) transporters in potentiating drug sensitivity

The role of Brugia malayi ATP-binding cassette (ABC) transporters in potentiating drug sensitivity

Ivermectin disrupts the function of the excretory-secretory apparatus in microfilariae of Brugia malayi

In Vitro Efficacy of Moxidectin versus Ivermectin against Sarcoptes scabiei

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