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Research on anthelmintic drugs, with an emphasis on structure-activity relationship and pharmacokinetic studies

Cowan, Noemi. Research on anthelmintic drugs, with an emphasis on structure-activity relationship and pharmacokinetic studies. 2015, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_12018

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Abstract

More than one third of the world’s population is infected with at least one helminth, among which schistosomiasis and trichuriasis are highly prevalent. The control of schistosomiasis relies heavily on the treatment of people living in endemic areas with praziquantel. Praziquantel is currently the only available antischistosomal drug and 28 million patients are treated every year, which leads to a high drug pressure on schistosomes. The low efficacy on the juvenile stage of Schistosoma and the risk of development of drug resistance urges the development of an alternative treatment.
The current chemotherapy of trichuriasis, using two benzimidazoles albendazole and mebendazole, results in unsatisfactory treatment outcomes. The co-administration of the two drugs cures more trichuriasis patients than the drugs administered separately. Also the co-administration of albendazole with the rediscovered trichuricidal drug oxantel pamoate is a promising treatment. In order to apply these coadministrations on the large scale, safety has to be assured.
The objectives of this thesis were to advance the development of antischistosomal drugs by conducting structure-activity relationship studies and by defining new
pharmacophores for lead optimization. Moreover, we aimed to determine the safety of two coadministrations (albendazole plus oxantel pamoate, and albendazole plus mebendazole) by studying their preclinical in vitro and in vivo drug-drug interactions.
Three compound sets were investigated for antischistosomal activity by testing them first against the larval and adult stage of S. mansoni, followed by a cytotoxicity determination to finally evaluate the in vivo efficacy in the chronic S. mansoni mouse model. The first set tested consisted of five different synthetic peroxide classes: bridged 1,2,4-trioxolanes, bridged 1,2,4,5-tetraoxanes, tricyclic monoperoxides, silyl peroxides, and hydroxylamine derivatives. The trioxolanes, tetraoxanes, and the tricyclic monoperoxides showed high in vitro activities in the low micromolar to nanomolar range. None of the compounds revealed significantly high drug efficacy in vivo. The highest efficacy was achieved by the trioxolane class displaying a worm burden reduction (WBR) of 44%. Since low solubility of the peroxides was noted and assumed to be a major limiting factor for drug efficacy, the peroxides were next packed into a cyclodextrin complex. However, the WBRs were unchanged. Further lead optimization of peroxides should aim to synthesize compounds with higher aqueous solubility. In a further project, we assessed the antischistosomal activities of MMV665852 analogs to identify new pharmacophores. N,N’-diarylureas, N-phenyl benzamides, and N-arylphenylcarbamates revealed high and fast in vitro activity at concentrations in the low micromolar to the nanomolar range within few hours of drug exposure. For high activity, the presence of a conjugated ring system on both sides of the structures was essential. The highest WBRs were observed with a N-phenyl benzamide 66%) and a N,N’-diarylurea (43%). For this drug set, we investigated the “drugability” of the compounds using in silico and in vitro tools, testing physico-chemical parameters, solubility, permeability through the intestinal wall, and metabolic stability. Solubility appeared to be the main reason for low “drugability” of the compounds. Also this set of molecules demonstrated the necessity of the compound to have drug-like features. Therefore, it is recommended to apply a “structure-bioavailabilityactivity”-based drug design and screen flow. Several marketed cancer drugs contain the N,N’-diarylurea or N-phenyl benzamide structures. Additionally, cancer drugs are believed to target drug action present in schistosomes and in humans. For these reasons, a cancer drug library of 114 compounds was tested for antischistosomal activity. Eleven drugs demonstrated in vitro activity below 10 μM, of which two demonstrated in vivo activity (trametinib: 64% WBR, vandetanib: 48% WBR). Future studies might involve multiple administrations of the drugs to simulate their long halflives in humans, which are short in the mouse, or the assessment of the drugs’ influence on schistosome development, with which cancer drugs were suggested to interfere.
The potential for drug-drug interactions of albendazole plus mebendazole and albendazole plus oxantel pamoate was assessed using two approaches: first, using an in vitro metabolic assay, assessing the inhibition of Cytochrome P450 (CPY), and second, comparising pharmacokinetic parameters after applying co-administrations or monotherapy to rats. The in vitro CYP inhibition assay showed only interaction against CYP1A2. In more detail, this interaction was presented by a 2.6-fold decreased IC50 value, when the enzyme was simultaneously exposed to albendazole and oxantel pamoate compared to separate exposures. For analysis of the plasma concentrations from the in vivo study, a High Pressure Liquid Chromatography (HPLC) method with UV detection was developed for oxantel pamoate, albendazole sulfoxide and sulfone (the two major metabolites of albendazole), and mebendazole and validated according to FDA guidelines. No interaction between albendazole and oxantel pamoate was observed in vivo, presumably due to low bioavailability of oxantel pamoate. However, a moderate interaction was observed in the disposition of mebendazole. Mebendazole co-administered with albendazole resulted in a significantly increased area under the plasma curve (AUC) (3.5-fold increase) and a maximal plasma concentration (Cmax)(2.8-fold increase). However, the observed interaction might not apply to humans, since the plasma levels observed in humans, after the standard treatment dosages are ten to thirty times
lower than the levels we observed in rats. It is further not known what role the species differences of the quantitative biotransformation of benzimidazole plays. Therefore, further safety studies on co-administration albendazole plus mebendazole in healthy humans might be needed to confirm the safety of the regimen. A safety study of the co-administration albendazole plus oxantel pamoate may only be considered, if tests for absorption and bioavailability of oxantel pamoate indicate exposure of the body to oxantel pamoate.
In conclusion, the projects of antischistosomal drug discovery identified new active pharmacophores and provided evidence for the hypothesized antischistosomal activity of cancer drugs. The pharmacokinetic safety evaluation detected a potential interaction when albendazole and mebendazole are co-administered.
Advisors:Utzinger, Jürg and Keiser, Jennifer and Olliaro, Piero
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Epidemiology and Public Health (EPH) > Eco System Health Sciences > Health Impact Assessment (Utzinger)
Item Type:Thesis
Thesis no:12018
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (VIII, 88 Seiten)
Language:English
Identification Number:
Last Modified:10 Feb 2017 11:03
Deposited On:10 Feb 2017 11:03

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