Unresolved issues in anthelmintic pharmacology for helminthiases of humans

Geary, Timothy G.; Woo, Katherine; McCarthy, James S.; Mackenzie, Charles D.; Horton, John; Prichard, Roger K.; Silva, Nilanthi R. de; Olliaro, Piero; Lazdins-Helds, Janis K.; Engels, Dirk; Bundy, Donald

doi:10.1016/j.ijpara.2009.11.001

Cited by 202 publications

(171 citation statements)

References 103 publications

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“…Second, as no other sites of expression of GluCl subunits were observed, muscle activity in this area of mf must account for the mechanism of action of this drug against this stage. 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).…”

Section: Discussionsupporting

confidence: 66%

“…Despite the remarkable reduction in morbidity and profound interruption of disease transmission achieved by the MDA programs for the control of onchocerciasis and LF (1), there are concerns about the feasibility of eliminating filarial infections without the availability of a macrofilaricide in the short term; additional concerns about the possible emergence of resistance to IVM, which forms a mainstay of both programs (23,24), ex- acerbate the need to attain a much better understanding of the pharmacology of existing antifilarial drugs, which remains poor (5). Inadequate understanding of the basis for the action of IVM on these parasites impedes our ability to optimize its clinical use and to sustain the efficacy of the drug in the mid-to long-term.…”

Section: Discussionmentioning

confidence: 99%

“…IVM, a macrocyclic lactone endectocide, is considered a microfilaricide because of the fast mf clearance observed and the extremely prolonged suppression of their reappearance after dosing (5). Although kinetics of mf clearance vary depending on the species, most of the dramatic changes in the mf load take place during the first week of treatment.…”

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confidence: 99%

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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.

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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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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

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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.

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147

141

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“…We were interested in re-infection patterns after treatment, but this proved to be difficult to determine for T. trichiura as only a few of the infections completely cleared even after triple-dose albendazole administration. 45,46 Interestingly, hookworm infections were greatly reduced by triple-dose albendazole and the resulting low prevalence was maintained over the 6-month follow-up period, whereas prevalences of A. lumbricoides and T. trichiura were steadily increasing. Re-infection with hookworm is known to be slower compared with other common soil-transmitted helminth species as the reproductive number (R 0 ) of hookworm is the lowest among them, 6 and the time between the 1-and 4-month follow-ups (December-March) was cold and dry, conditions known to be unsuitable for the development and survival of hookworm larvae.…”

Section: Discussionmentioning

confidence: 99%

Rapid Re-Infection with Soil-Transmitted Helminths after Triple-Dose Albendazole Treatment of School-Aged Children in Yunnan, People's Republic of China

Yap

Du²,

Fang-wei³

et al. 2013

The American Society of Tropical Medicine and Hygiene

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Abstract. Post-treatment soil-transmitted helminth re-infection patterns were studied as part of a randomized controlled trial among school-aged children from an ethnic minority group in Yunnan province, People's Republic of China. Children with a soil-transmitted helminth infection (N = 194) were randomly assigned to triple-dose albendazole or placebo and their infection status monitored over a 6-month period using the Kato-Katz and Baermann techniques. Baseline prevalence of Trichuris trichiura, Ascaris lumbricoides, hookworm, and Strongyloides stercoralis were 94.5%, 93.3%, 61.3%, and 3.1%, respectively, with more than half of the participants harboring triple-species infections. For the intervention group (N = 99), the 1-month post-treatment cure rates were 96.7%, 91.5%, and 19.6% for hookworm, A. lumbricoides, and T. trichiura, respectively. Egg reduction rates were above 88% for all three species. Rapid re-infection with A. lumbricoides was observed: the prevalence 4 and 6 months post-treatment was 75.8% and 83.8%, respectively. Re-infection with hookworm and T. trichiura was considerably slower.

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“…Thus, we conclude that human KCNMA1 can functionally substitute for the nematode channel SLO-1 in vivo and that the two channels exhibit distinct pharmacological properties. With regard to the selective toxicity of emodepside and the potential of the new class of cyclooctodepsipeptides in tropical medicine for filariasis (Geary et al, 2010), the C. elegans channel is 10-to 100-fold more sensitive to emodepside than the human channel.…”

Section: Introductionmentioning

confidence: 99%

Selective Toxicity of the Anthelmintic Emodepside Revealed by Heterologous Expression of Human KCNMA1 inCaenorhabditis elegans

Crisford¹,

Murray²,

O’Connor³

et al. 2011

Mol Pharmacol

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Emodepside is a resistance-breaking anthelmintic of a new chemical class, the cyclooctadepsipeptides. A major determinant of its anthelmintic effect is the calcium-activated potassium channel SLO-1. SLO-1 belongs to a family of channels that are highly conserved across the animal phyla and regulate neurosecretion, hormone release, muscle contraction, and neuronal network excitability. To investigate the selective toxicity of emodepside, we performed transgenic experiments in which the nematode SLO-1 channel was swapped for a mammalian ortholog, human KCNMA1. Expression of either the human channel or Caenorhabditis elegans slo-1 from the native slo-1 promoter in a C. elegans slo-1 functional null mutant rescued behavioral deficits that otherwise resulted from loss of slo-1 signaling. However, worms expressing the human channel were 10-to 100-fold less sensitive to emodepside than those expressing the nematode channel. Strains expressing the human KCNMA1 channel were preferentially sensitive to the mammalian channel agonists NS1619 and rottlerin. In the C. elegans pharyngeal nervous system, slo-1 is expressed in neurons, not muscle, and cell-specific rescue experiments have previously shown that emodepside inhibits serotonin-stimulated feeding by interfering with SLO-1 signaling in the nervous system. Here we show that ectopic overexpression of slo-1 in pharyngeal muscle confers sensitivity of the muscle to emodepside, consistent with a direct interaction of emodepside with the channel. Taken together, these data predict an emodepside-selective pharmacophore harbored by SLO-1. This has implications for the development of this drug/ target interface for the treatment of helminth infections.

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Unresolved issues in anthelmintic pharmacology for helminthiases of humans

Cited by 202 publications

References 103 publications

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

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

Rapid Re-Infection with Soil-Transmitted Helminths after Triple-Dose Albendazole Treatment of School-Aged Children in Yunnan, People's Republic of China

Selective Toxicity of the Anthelmintic Emodepside Revealed by Heterologous Expression of Human KCNMA1 inCaenorhabditis elegans

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