Itraconazole, a cytochrome P450 inhibitor, enhanced the efficacy of praziquantel against Schistosoma mansoni infection and alleviated liver injury in mice

Theodor Bilharz Research Institute

Bibliographic Information

Authors: Sabra A.-N.A.; Salem M.B.; William S.; Hammam O.A.; El-Lakkany N.M.

Journal: Experimental Parasitology

Publisher: Academic Press Inc.

Publication Date: August 2022

Volume / Issue: Volume 239

Article No.: 108293

ISSN: 144894

DOI: 10.1016/j.exppara.2022.108293

Scopus: View on Scopus

PubMed: 35667394

Document Type: Article

Authors and Affiliations

Sabra A.-N.A., Professor of Pharmacology, Theodor Bilharz Research Institute, Giza, Egypt; Salem M.B., Lecturer of Pharmacology, Theodor Bilharz Research Institute, Giza, Egypt; William S., Professor of Parasitology, Theodor Bilharz Research Institute, Giza, Egypt; Hammam O.A., Professor of Pathology, Theodor Bilharz Research Institute, Giza, Egypt; El-Lakkany N.M., Professor of Pharmacology, Theodor Bilharz Research Institute, Giza, Egypt

Abstract

Treatment of schistosomiasis is heavily reliant on the single antischistosomal drug praziquantel (PZQ). The use of synergistic drug-drug interactions is one possible solution, which could be used to mitigate PZQ's poor and variable bioavailability. Itraconazole (ITZ), a triazole antifungal agent, is a potent CYP3A inhibitor that can cause significant drug-drug interactions when used with CYP3A substrates. This study investigates the effect of ITZ as adjuvant therapy with PZQ on worm load, egg deposition and maturation, and the consequent histopathology and biochemical abnormalities in the liver during the immature and mature stages of Schistosoma mansoni (S. mansoni) infection. S. mansoni-infected mice were divided into five groups of eight−ten mice each: (I) infected untreated, (II) infected and treated with PZQ 3 weeks PI, (III) infected and treated with both ITZ and PZQ 3 weeks PI, (IV) infected and treated with PZQ 7 weeks PI, and (V) infected and treated with both ITZ and PZQ 7 weeks PI. All mice were killed by rapid decapitation 9 weeks PI. Data revealed that ITZ in combination with PZQ at both immature and mature stages improved the parasitological criteria of cure, and greatly reduced inflammation, granuloma and fibrotic tissue formation, and apoptosis versus PZQ alone. Furthermore, it showed the greatest impact on improving liver injury and oxidative stress markers. Notably, the effect was considerably stronger at the mature stage of S. mansoni infection. These findings support the notion that ITZ increased PZQ's antischistosomal activity by inhibiting CYP450 expression, potentially reducing PZQ metabolism and increasing systemic exposure. © 2022 Elsevier Inc.

Keywords

Caspase 3; CYP450; Granuloma; Itraconazole; Praziquantal; Schistosoma mansoni; Animals; Anthelmintics; Liver; Mice; Praziquantel; Schistosomiasis mansoni; cytochrome P450; itranox; anthelmintic agent; adjuvant therapy; adult; animal experiment; animal model; animal tissue; anthelmintic activity; antiinflammatory activity; apoptosis; Article; combination drug therapy; controlled study; drug bioavailability; drug blood level; drug efficacy; drug elimination; drug exposure; drug metabolism; drug potency; drug potentiation; histopathology; in vitro study; in vivo study; liver fibrosis; liver granuloma; liver injury; male; monotherapy; mouse; nonhuman; oxidative stress; protein expression; single drug dose; worm burden; animal; pathology

Citation Information

Scopus Citations: 3

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