Reduction of <i>Loa loa</i> Microfilaremia with Imatinib — A Case Report

O’Connell, Elise M.; Nutman, Thomas B.

doi:10.1056/nejmc1712990

Cited by 9 publications

(6 citation statements)

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“…These results motivate for further validation in animal studies. In case of imatinib, serum proteins such as alpha-1-acid glycoprotein (AGP) were shown to bind the drug, which reduced its in vivo efficacy against schistosomes using rodents as model host (72). More motivating was a case report on orally administered imatinib in a human filariasis patient, which reduced worm burden (73).…”

Section: Discussionmentioning

confidence: 99%

“…More motivating was a case report on orally administered imatinib in a human filariasis patient, which reduced worm burden (73). Thus, when it comes to in vivo studies, it needs to be considered that the degree of drug-plasma protein binding varies between species, especially between rodents and human (72). AGP concentrations vary between healthy to pathological states, and AGP exhibits species-dependent binding affinities (74)(75)(76).…”

Section: Discussionmentioning

confidence: 99%

“…In case of imatinib, serum proteins such as alpha-1-acid glycoprotein (AGP) were shown to bind the drug, which reduced its in vivo efficacy against schistosomes using rodents as model host ( 72 ). More motivating was a case report on orally administered imatinib in a human filariasis patient, which reduced worm burden ( 73 ). Thus, when it comes to in vivo studies, it needs to be considered that the degree of drug-plasma protein binding varies between species, especially between rodents and human ( 72 ).…”

Section: Discussionmentioning

confidence: 99%

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Targeting Kinases in Fasciola hepatica: Anthelminthic Effects and Tissue Distribution of Selected Kinase Inhibitors

et al. 2020

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Protein kinases have been discussed as promising druggable targets in various parasitic helminths. New drugs are also needed for control of fascioliasis, a food-borne trematode infection and worldwide spread zoonosis, caused by the liver fluke Fasciola hepatica and related species. In this study, we intended to move protein kinases more into the spotlight of Fasciola drug research and characterized the fasciolicidal activity of two small-molecule inhibitors from human cancer research: the Abelson tyrosine kinase (ABL-TK) inhibitor imatinib and the polo-like 1 (PLK1) inhibitor BI2536. BI2536 reduced viability of 4-week-old immature flukes in vitro, while adult worms showed a blockade of egg production. Together with a significantly higher transcriptional expression of PLK1 in adult compared to immature worms, this argues for a role of PLK1 in fluke reproduction. Both fluke stages expressed ABL1-TK transcripts at similar high levels and were affected by imatinib. To study the uptake kinetic and tissue distribution of imatinib in F. hepatica, we applied matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) for the first time in this parasite. Drug imaging revealed the accumulation of imatinib in different fluke tissues from 20 min to 12 h of exposure. Furthermore, we show that imatinib is metabolized to N-desmethyl imatinib by F. hepatica, a bioactive metabolite also found in humans. Besides the vitellarium, gastrodermal tissue showed strong signal intensities. In situ hybridization demonstrated the gastrodermal presence of abl1 transcripts. Finally, we assessed transcriptional changes of physiologically important genes in imatinib-treated flukes. Moderately increased transcript levels of a gene encoding a multidrug resistance protein were detected, which may reflect an attempt to defend against imatinib. Increased expression levels of the cell cycle dependently expressed histone h2b and of two genes encoding superoxide dismutases (SODs) were also observed. In summary, our pilot study demonstrated cross-stage activity of imatinib but not BI2536 against immature and adult F. hepatica in vitro; a fast incorporation of imatinib within minutes, probably via the oral route; and imatinib-induced expression changes of physiologically relevant genes. We conclude that kinases are worth analyzing in more detail to evaluate the potential as therapeutic targets in F. hepatica.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Targeting Kinases in Fasciola hepatica: Anthelminthic Effects and Tissue Distribution of Selected Kinase Inhibitors

et al. 2020

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“…Beyond that, imatinib has also shown activity against S. japonicum [86], Echinococcus multilocularis [87], Fasciola hepatica [88], Brugia malayi [89], Loa loa [90], Leishmania major [91], Giardia lamblia [92], and it prevented erythrocyte egress of Plasmodium falciparum [93]. In a case report, a single 600 mg dose of imatinib was even shown to reduce the number of microfilariae in a patient infected with L. loa [94]. Analysis of the route of imatinib uptake, its tissue tropism, and metabolization in schistosomes was recently achieved by a technique called MALDI mass spectrometry imaging [95] (Figure 4) and can likely be adopted for the study of other PTK inhibitors.…”

Section: Protein Kinases As Central Targets For Drug Repurposingmentioning

confidence: 99%

“…microfilariae in a patient infected with L. loa [94]. Analysis of the route of imatinib uptake, its tissue tropism, and metabolization in schistosomes was recently achieved by a technique called MALDI mass spectrometry imaging [95] (Figure 4) and can likely be adopted for the study of other PTK inhibitors.…”

Section: Protein Kinases As Central Targets For Drug Repurposingmentioning

confidence: 99%

Drug Repurposing and De Novo Drug Discovery of Protein Kinase Inhibitors as New Drugs against Schistosomiasis

et al. 2022

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Schistosomiasis is a neglected tropical disease affecting more than 200 million people worldwide. Chemotherapy relies on one single drug, praziquantel, which is safe but ineffective at killing larval stages of this parasite. Furthermore, concerns have been expressed about the rise in resistance against this drug. In the absence of an antischistosomal vaccine, it is, therefore, necessary to develop new drugs against the different species of schistosomes. Protein kinases are important molecules involved in key cellular processes such as signaling, growth, and differentiation. The kinome of schistosomes has been studied and the suitability of schistosomal protein kinases as targets demonstrated by RNA interference studies. Although protein kinase inhibitors are mostly used in cancer therapy, e.g., for the treatment of chronic myeloid leukemia or melanoma, they are now being increasingly explored for the treatment of non-oncological conditions, including schistosomiasis. Here, we discuss the various approaches including screening of natural and synthetic compounds, de novo drug development, and drug repurposing in the context of the search for protein kinase inhibitors against schistosomiasis. We discuss the status quo of the development of kinase inhibitors against schistosomal serine/threonine kinases such as polo-like kinases (PLKs) and mitogen-activated protein kinases (MAP kinases), as well as protein tyrosine kinases (PTKs).

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Clinical Aspects: Treatment of Simple and Complicated Forms of Loiasis

Klion

2023

Loa Loa: Latest Advances in Loiasis Research

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Reduction of Loa loa Microfilaremia with Imatinib — A Case Report

Cited by 9 publications

References 5 publications

Targeting Kinases in Fasciola hepatica: Anthelminthic Effects and Tissue Distribution of Selected Kinase Inhibitors

Targeting Kinases in Fasciola hepatica: Anthelminthic Effects and Tissue Distribution of Selected Kinase Inhibitors

Drug Repurposing and De Novo Drug Discovery of Protein Kinase Inhibitors as New Drugs against Schistosomiasis

Clinical Aspects: Treatment of Simple and Complicated Forms of Loiasis

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