Potential Drug Development Candidates for Human Soil-Transmitted Helminthiases

Olliaro, Piero; Seiler, J.P.; Kuesel, Annette C.; Horton, John; Clark, J. R.; Don, Robert; Keiser, Jennifer

doi:10.1371/journal.pntd.0001138

Cited by 84 publications

(61 citation statements)

References 48 publications

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“…First, the acute response of hookworm infection to K11777 is commensurate with the short (preferably single) oral dosing regimen currently employed for the MDA of anthelmintics [2], [17], [65]. Second, given that K11777 is already being targeted for submission as an IND to treat Chagas' disease, the inhibitor could also be tested as an experimental drug for hookworm disease.…”

Section: Discussionmentioning

confidence: 96%

Cure of Hookworm Infection with a Cysteine Protease Inhibitor

2012

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BackgroundHookworm disease is a major global health problem and principal among a number of soil-transmitted helminthiases (STHs) for the chronic disability inflicted that impacts both personal and societal productivity. Mass drug administration most often employs single-dose therapy with just two drugs of the same chemical class to which resistance is a growing concern. New chemical entities with the appropriate single-dose efficacy are needed.Methods and FindingsUsing various life-cycle stages of the hookworm Ancylostoma ceylanicum in vitro and a hamster model of infection, we report the potent, dose-dependent cidal activities of the peptidyl cysteine protease inhibitors (CPIs) K11002 (4-mopholino-carbonyl-phenylalanyl-homophenylalanyl- vinyl sulfone phenyl) and K11777 (N-methylpiperazine-phenylalanyl-homophenylalanyl-vinylsulfone phenyl). The latter is in late pre-clinical testing for submission as an Investigational New Drug (IND) with the US Federal Drug Administration as an anti-chagasic. In vitro, K11002 killed hookworm eggs but was without activity against first-stage larvae. The reverse was true for K11777 with a larvicidal potency equal to that of the current anti-hookworm drug, albendazole (ABZ). Both CPIs produced morbidity in ex vivo adult hookworms with the activity of K11777 again being at least the equivalent of ABZ. Combinations of either CPI with ABZ enhanced morbidity compared to single compounds. Strikingly, oral treatment of infected hamsters with 100 mg/kg K11777 b.i.d. (i.e., a total daily dose of 200 mg/kg) for one day cured infection: a single 100 mg/kg treatment removed >90% of worms. Treatment also reversed the otherwise fatal decrease in blood hemoglobin levels and body weights of hosts. Consistent with its mechanism of action, K11777 decreased by >95% the resident CP activity in parasites harvested from hamsters 8 h post-treatment with a single 100 mg/kg oral dose.ConclusionA new, oral single-dose anthelmintic that is active in an animal model of hookworm infection and that possesses a distinct mechanism of action from current anthelmintics is discovered. The data highlight both the possibility of repurposing the anti-chagasic K11777 as a treatment for hookworm infection and the opportunity to further develop CPIs as a novel anthelmintic class to target hookworms and, possibly, other helminths.

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Section: Discussionmentioning

confidence: 96%

Cure of Hookworm Infection with a Cysteine Protease Inhibitor

2012

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“…In particular, combinations of albendazole plus ivermectin, albendazole plus mebendazole, and albendazole plus oxantel pamoate have been investigated in randomized controlled trials in the past years (2,3,6). A key characteristic for anthelmintic treatment is the almost compulsory usage of single-dose regimens (26), since the treatments are used at large scale in preventive chemotherapy programs. Therefore, a combined delivery of drugs to the population is warranted.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo Drug Interaction Study of Two Lead Combinations, Oxantel Pamoate plus Albendazole and Albendazole plus Mebendazole, for the Treatment of Soil-Transmitted Helminthiasis

Cowan

Vargas

Keiser

2016

Antimicrob Agents Chemother

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bThe current treatments against Trichuris trichiura, albendazole and mebendazole, are only poorly efficacious. Therefore, combination chemotherapy was recommended for treating soil-transmitted helminthiasis. Albendazole-mebendazole and albendazole-oxantel pamoate have shown promising results in clinical trials. However, in vitro and in vivo drug interaction studies should be performed before their simultaneous treatment can be recommended. Inhibition of human recombinant cytochromes P450 (CYPs) CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 was tested by exposure to albendazole, albendazole sulfoxide, mebendazole, and oxantel pamoate, as well as albendazole-mebendazole, albendazole sulfoxide-mebendazole, albendazole-oxantel pamoate, and albendazole sulfoxide-oxantel pamoate. A high-pressure liquid chromatography (HPLC)-UV/visible spectroscopy method was developed and validated for simultaneous quantification of albendazole sulfoxide, albendazole sulfone, mebendazole, and oxantel pamoate in plasma. Albendazole, mebendazole, oxantel pamoate, albendazole-mebendazole, and albendazole-oxantel pamoate were orally applied to rats (100 mg/kg) and pharmacokinetic parameters calculated. CYP1A2 showed a 2.6-fold increased inhibition by albendazole-oxantel pamoate (50% inhibitory concentration [IC 50 ] ‫؍‬ 3.1 M) and a 3.9-fold increased inhibition by albendazole sulfoxide-mebendazole (IC 50 ‫؍‬ 3.8 M) compared to the single drugs. In rats, mebendazole's area under the concentration-time curve (AUC) and maximal plasma concentration (C max ) were augmented 3.5-and 2.8-fold, respectively (P ‫؍‬ 0.02 for both) when coadministered with albendazole compared to mebendazole alone. Albendazole sulfone was slightly affected by albendazole-mebendazole, displaying a 1.3-fold-elevated AUC compared to albendazole alone. Oxantel pamoate could not be quantified, translating to a bioavailability below 0.025% in rats. Elevated plasma levels of albendazole sulfoxide, albendazole sulfone, and mebendazole in coadministrations are probably not mediated by CYP-based drug-drug interaction. Even though this study indicates that it is safe to coadminister albendazole-oxantel pamoate and albendazole-mebendazole, human pharmacokinetic studies are recommended.A n estimated 465 million people are infected with the soiltransmitted helminth (STH) Trichuris trichiura, also known as human whipworm (1). Treatment programs (preventive chemotherapy) using the benzimidazoles albendazole and mebendazole are implemented to deworm patients infected with STHs. However, both drugs show low efficacy in single-dose treatment regimens (2, 3, 36).To make a step toward better treatment options for trichuriasis (4), combination therapies have received increased attention in the recent past. In more detail, in a recent study in Uganda, albendazole coadministered with mebendazole cured 54.2% of infections and reduced egg excretion by 94.3%, as opposed to low cure rates of single treatments with albendazole (15.4% cure rate; 54.9% egg reduction rate) and mebendazole (20.4% cur...

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“…the two veterinary products, emodepside (currently very expensive) and monepantel (activity against STH is currently being assessed, personal communication), and tribendimidine and nitazoxanide, which have been approved for human use but still have limited utility (Xiao et al, 2005;Olliaro et al, 2011). Should AR arise imminently and spread, at a time when our anthelmintic armoury is still so limited, we may have to resort to traditional methods of control based on improvements in sanitation, education to change human behaviour and to ensure that footwear is more widely adopted in the case of hookworm control.…”

Section: Subjectmentioning

confidence: 99%

Is anthelmintic resistance a concern for the control of human soil-transmitted helminths?

Vercruysse

Albonico²,

Behnke

et al. 2011

International Journal for Parasitology: Drugs and Drug Resistan

240

220

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The major human soil-transmitted helminths (STH), Ascaris lumbricoides, hookworms (Necator americanus and Ancylostoma duodenale) and Trichuris trichiura have a marked impact on human health in many parts of the world. Current efforts to control these parasites rely predominantly on periodic mass administration of anthelmintic drugs to school age children and other at-risk groups. After many years of use of these same drugs for controlling roundworms in livestock, high levels of resistance have developed, threatening the sustainability of these livestock industries in some locations. Hence, the question arises as to whether this is likely to also occur in the human STH, thereby threatening our ability to control these parasites. This is particularly important because of the recent increase in mass control programmes, relying almost exclusively on benzimidazole anthelmintics. It will be important to ensure that resistance is detected as it emerges in order to allow the implementation of mitigation strategies, such as use of drug combinations, to ensure that the effectiveness of the few existing anthelmintic drugs is preserved. In this review we address these issues by firstly examining the efficacy of anthelmintics against the human STH, and assessing whether there are any indications to date that resistance has emerged. We then consider the factors that influence the effect of current drug-use patterns in selecting for resistant parasite populations. We describe the tools currently available for resistance monitoring (field-based coprological methods), and those under development (in vitro bioassays and molecular tests), and highlight confounding factors that need to be taken into account when interpreting such resistance-monitoring data. We then highlight means to ensure that the currently available tools are used correctly, particularly with regard to study design, and we set appropriate drug-efficacy thresholds. Finally, we make recommendations for monitoring drug efficacy in the field, as components of control programmes, in order to maximise the ability to detect drug resistance, and if it arises to change control strategy and prevent the spread of resistance.

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Potential Drug Development Candidates for Human Soil-Transmitted Helminthiases

Cited by 84 publications

References 48 publications

Cure of Hookworm Infection with a Cysteine Protease Inhibitor

Cure of Hookworm Infection with a Cysteine Protease Inhibitor

In Vitro and In Vivo Drug Interaction Study of Two Lead Combinations, Oxantel Pamoate plus Albendazole and Albendazole plus Mebendazole, for the Treatment of Soil-Transmitted Helminthiasis

Is anthelmintic resistance a concern for the control of human soil-transmitted helminths?

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