In vitro studies on the relative sensitivity to ivermectin of Necator americanus and Ancylostoma ceylanicum

Richards, Jenny; Behnke, Jerzy M.; Duce, I.R.

doi:10.1016/0020-7519(95)00036-2

Cited by 46 publications

(36 citation statements)

References 17 publications

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“…Multiple studies investigating hookworm susceptibility to anthelmintics have reported that lower drug concentrations are effective against A. ceylanicum compared with N. americanus. 7,[38][39][40] These observations are supported by our comparative studies of the half-maximal inhibitory concentration (IC 50 ) values for ABZ and pyrantel pamoate (Table 4). For both compounds, higher IC 50 values were recorded for field isolates of hookworm compared with A. ceylanicum.…”

supporting

confidence: 70%

In vitro Screening of Compounds against Laboratory and Field Isolates of Human Hookworm Reveals Quantitative Differences in Anthelmintic Susceptibility

Treger

Otchere

Keil

et al. 2014

The American Society of Tropical Medicine and Hygiene

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Abstract. A panel of 80 compounds was screened for anthelmintic activity against a laboratory strain of Ancylostoma ceylanicum and field isolates of hookworm obtained from school children in the Kintampo North District of the Brong Ahafo Region of Ghana. Although the laboratory strain of A. ceylanicum was more susceptible to the compounds tested than the field isolates of hookworm, a twofold increase in compound concentration resulted in comparable egg hatch percent inhibition for select compounds. These data provide evidence that the efficacy of anthelmintic compounds may be species-dependent and that field and laboratory strains of hookworm differ in their sensitivities to the anthelmintics tested. These data also suggest that both compound concentration and hookworm species must be considered when screening to identify novel anthelmintic compounds.Human hookworm disease results from infection by two genera of hookworms, Ancylostoma spp. and Necator americanus. Albendazole (ABZ) and mebendazole (MBZ) are the primary drugs used to treat hookworm infection. A recent meta-analysis and review of field-based studies have shown that single-dose treatment cure rates with ABZ and MBZ are low (72% and 15%, respectively).1,2 Compounding these treatment failure rates in humans is the well-documented emergence of drug resistance to ABZ and MBZ among parasitic nematodes of agricultural and veterinary importance. [3][4][5] In light of this information, the development of novel anthelmintic chemotherapeutics is necessary.Currently, the identification and development of novel anthelmintic compounds to cure hookworm infection rely on laboratory-based screening for inhibitors of egg hatching, larval motility and morphology, and/or adult worm survival.6-9 However, novel compounds identified using small animal models of hookworm infection are rarely screened for comparable activity against field isolates of human hookworms. [10][11][12][13][14][15][16] Therefore, the correlation between the anthelmintic activity of compounds against laboratory and field isolates of human hookworms remains largely unknown.Moreover, for those cases in which anthelmintic activity is investigated, the larvicidal, rather than ovicidal, properties of a compound are usually analyzed. [17][18][19][20] Ovicidal activity is more frequently and most readily assayed in resource-limited field settings, where larval and adult hookworm-based assays are impractical tools for assessing anthelmintic activity. [21][22][23]

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supporting

confidence: 70%

In vitro Screening of Compounds against Laboratory and Field Isolates of Human Hookworm Reveals Quantitative Differences in Anthelmintic Susceptibility

Treger

Otchere

Keil

et al. 2014

The American Society of Tropical Medicine and Hygiene

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“…As with other studies utilizing inulin as a marker of ingestion (16,36), the continued recovery of some inulin as the ivermectin concentration increased above 10 nM was expected and is probably due to adherence of the carbohydrate to the external surface of the worm rather than ingestion. The effectiveness of 10 nM ivermectin in preventing uptake by ingestion was confirmed using FITC-labeled dextran (molecular mass, 40 kDa) as shown in Fig.…”

Section: Resultsmentioning

confidence: 57%

“…4). As mentioned above, inulin is considered too large to pass through the nematode cuticle, and hence [ 3 H]inulin has been used as a marker for nematode feeding in numerous studies (16,36,45). A disadvantage with its use is that some inulin is recovered along with ligated worms, as shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

Cyclotide Interactions with the Nematode External Surface

Colgrave

Huang

Craik

et al. 2010

Antimicrob Agents Chemother

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Cyclotides are a large family of cyclic cystine knot-containing plant peptides that have anthelminthic activities against Haemonchus contortus and Trichostrongylus colubriformis, two important gastrointestinal nematodes of sheep. In this study, we investigated the interaction of the prototypic cyclotide kalata B1 with the external surface of H. contortus larvae and adult worms. We show that cyclotides do not need to be ingested by the worms to exert their toxic effects but that an interaction with the external surface alone is toxic. Evidence for this was the toxicity toward adult worms in the presence of a chemically induced pharyngeal ligature and toxicity of cyclotides toward nonfeeding larval life stages. Uptake of tritiated inulin in ligated adult worms was increased in the presence of cyclotide, suggesting that cyclotides increase the permeability of the external membranes of adult nematodes. Polyethylene glycols of various sizes showed protective effects on the nonfeeding larval life stage, as well as in hemolytic activity assays, suggesting that discrete pores are formed in the membrane surfaces by cyclotides and that these can be blocked by polyethylene glycols of appropriate size. This increased permeability is consistent with recently reported effects of cyclotides on membranes in which kalata B1 was demonstrated to form pores and cause leakage of vesicle/cellular contents. Our data, together with known size constraints on the movement of permeants across nematode cuticle layers, suggest that one action of the cyclotides involves an interaction with the lipid-rich epicuticle layer at the surface of the worm.Cyclotides are disulfide-rich peptides from plants that are characterized by their cyclic peptide backbone; they are the largest known family of genetically encoded cyclic proteins (11,23,46). More than 140 cyclotides have been reported to exist in the Violaceae and Rubiaceae plant families, and this number is expanding rapidly. Recent investigations suggest that thousands more cyclotides have yet to be discovered (46). Cyclotides exhibit a diverse range of biological activities, including anti-HIV (17, 22), antimicrobial (50), antineurotensin (52), cytotoxic (28, 49), and hemolytic (3, 40) activities. It has been postulated that the natural function of cyclotides is one of defense against plant pests and pathogens (2,23,24). The cyclotides kalata B1 (kB1) and kalata B2 (kB2) have a dramatic effect on growth and development of Helicoverpa punctigera (23) and Helicoverpa armigera larvae (24), two major pests of cotton. Recently, we demonstrated that cyclotides isolated from the plant Oldenlandia affinis display anthelminthic activity toward the gastrointestinal parasitic nematodes Haemonchus contortus and Trichostrongylus colubriformis (8). Subsequent studies found that cycloviolacins (a group of cyclotides isolated from Viola odorata) showed up to an 18-foldincreased potency against these nematodes relative to the prototypic cyclotide, kB1 (9). More recently, selected cyclotides have been shown to ...

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“…Interestingly, the recently published genome of the hookworm Necator americanus [51] revealed that their GluCl channel genes appear to lack key residues for ivermectin activity, a finding which may explain the relatively low ivermectin sensitivity of these worms [52]. Schistosomes and other platyhelminths are typically not sensitive to macrocyclic lactones [53, 54] (though see [55]), which could suggest an absence of GluCl channels in these organisms.…”

Section: Glutamate-gated Chloride Channelsmentioning

confidence: 99%

Ion Channels and Drug Transporters as Targets for Anthelmintics

Greenberg

2014

Curr Clin Micro Rpt

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Infections with parasitic helminths such as schistosomes and soil-transmitted nematodes are hugely prevalent and responsible for a major portion of the global health and economic burdens associated with neglected tropical diseases. In addition, many of these parasites infect livestock and plants used in agriculture, resulting in further impoverishment. Treatment and control of these pathogens rely on anthelmintic drugs, which are few in number, and against which drug resistance can develop rapidly. The neuromuscular system of the parasite, and in particular, the ion channels and associated receptors underlying excitation and signaling, have proven to be outstanding targets for anthelmintics. This review will survey the different ion channels found in helminths, focusing on their unique characteristics and pharmacological sensitivities. It will also briefly review the literature on helminth multidrug efflux that may modulate parasite susceptibility to anthelmintics and may prove useful targets for new or repurposed agents that can enhance parasite drug susceptibility and perhaps overcome drug resistance.

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In vitro studies on the relative sensitivity to ivermectin of Necator americanus and Ancylostoma ceylanicum

Cited by 46 publications

References 17 publications

In vitro Screening of Compounds against Laboratory and Field Isolates of Human Hookworm Reveals Quantitative Differences in Anthelmintic Susceptibility

In vitro Screening of Compounds against Laboratory and Field Isolates of Human Hookworm Reveals Quantitative Differences in Anthelmintic Susceptibility

Cyclotide Interactions with the Nematode External Surface

Ion Channels and Drug Transporters as Targets for Anthelmintics

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