Efficacy, safety and pharmacokinetics of 1,2,4-trioxolane OZ78 against an experimental infection with Fasciola hepatica in sheep

Leishmaniasis is among the world's most neglected diseases. Currently available drugs for treatment present drawbacks, urging the need for more effective, safer, and cheaper drugs. A small library of artemisinin-derived trioxanes and synthetic trioxolanes was tested against promastigote and intramacrophage amastigote forms of Leishmania infantum. The trioxolanes LC50 and LC95 presented the best activity and safety profiles, showing potential for further studies in the context of leishmanial therapy. Our results indicate that the compounds tested exhibit peroxide-dependent activity.

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confidence: 99%

In Vitro Susceptibility of Leishmania infantum to Artemisinin Derivatives and Selected Trioxolanes

Cortes

Albuquerque

Cabral

et al. 2015

“…Contradictory results were obtained in sheep. While OZ78 failed to cure a chronic F. hepatica infection in sheep (16), artemether and artesunate achieved high worm burden reductions in naturally F. hepatica-infected sheep (18,23).…”

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confidence: 99%

In Vivo and In Vitro Sensitivity of Fasciola hepatica to Triclabendazole Combined with Artesunate, Artemether, or OZ78

Duthaler

Smith

Keiser

2010

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Triclabendazole resistance is continually documented from livestock, and hence new treatment strategies for Fasciola hepatica infections are needed. We investigated the effect of triclabendazole combined with artesunate, artemether, or OZ78 compared to that of monotherapy against adult and juvenile F. hepatica in rats. In vitro experiments with triclabendazole and its sulfoxide and sulfone metabolites, each in combination with the peroxides, complemented our study. F. hepatica-infected rats were subjected to single drugs or drug combinations 3 to 4 weeks (juvenile flukes) and >8 weeks (adult flukes) postinfection. Negative binomial regressions of worm and egg counts were used to analyze dose-response relationships and whether the effects of drug combinations were synergistic or antagonistic. The in vitro assays were evaluated by means of viability scales based on fluke motility. Fifty percent effective dose values of 113.0, 77.7, 22.9, and 2.7 mg/kg of body weight were calculated for monotherapy with artesunate, artemether, OZ78, and triclabendazole, respectively, against adult F. hepatica. Likelihood ratio tests revealed synergistic interactions (P < 0.05) of combinations of triclabendazole (2.5 mg/kg) plus artesunate or artemether on adult worm burden. Antagonistic effects on the adult burden and egg output were observed when a lower triclabendazole dose (1.25 mg/kg) was combined with the artemisinins. No significant interactions (P ‫؍‬ 0.07) were observed for OZ78 and triclabendazole combinations and between the triclabendazole effect and the effects of the other partner drugs on juvenile worms. Our in vitro studies of adult worms agreed with the in vivo results, while the in vitro analysis of juvenile worms revealed greater interactions than observed in vivo. In conclusion, single-agent triclabendazole demonstrated a more potent in vivo and in vitro fasciocidal activity than the experimental drugs artesunate, artemether, and OZ78. When combined, synergistic but also antagonistic effects depending on the doses administered were observed, which should be elucidated in more detail in future studies.

“…The linear dynamic range of the OZ418 calibration curve, however, extended up to 1 g/ml only. Since the preliminary analysis of mouse plasma samples confirmed 10-to 100-fold-higher concentrations of OZ418 (as expected from the PK data for the other ozonides) (30,31,(53)(54)(55)64), dilution of samples was incorporated into sample preparation. The latter consisted of a simple protein precipitation with acetonitrile.…”

Section: Corresponding To [M ϫ Ch 2 C(o)oh]mentioning

confidence: 87%

“…So far, no enterohepatic recirculation has been reported for synthetic ozonides. A special feature of the OZ418 PK profile is its relatively long elimination half-life of 38.7 h (20.0 to 64.6 h), one of the longest half-lives reported for synthetic ozonides (29)(30)(31)(53)(54)(55). For comparison, the first generation of ozonides had a half-life of 1 to 2 h only, an improvement over the extremely short 0.5-h half-life of artesunate (29).…”

Section: Corresponding To [M ϫ Ch 2 C(o)oh]mentioning

confidence: 99%

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Pharmacokinetics of the Antischistosomal Lead Ozonide OZ418 in Uninfected Mice Determined by Liquid Chromatography-Tandem Mass Spectrometry

Leonidova

Vargas

Huwyler

et al. 2016

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One of the major neglected tropical diseases, schistosomiasis, is currently treated and controlled with a single drug, praziquantel. The quest for an alternative drug is fueled by the lack of activity of praziquantel against juvenile Schistosoma worms and the fear of emerging resistance. The synthetic ozonide OZ418 has shown high activity against Schistosoma mansoni, S. haematobium, and S. japonicum in vivo, but its drug disposition remains unknown. To bridge this gap, our study determined the basic pharmacokinetic (PK) parameters of a single oral dose (400 mg/kg of body weight) of OZ418 in uninfected mice. First, a simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify OZ418 concentrations in mouse plasma was successfully developed and validated according to U.S. FDA guidelines. This method proved to be selective, accurate (93 to 103%), precise (5 to 16%), and devoid of significant matrix effects (90 to 102%) and provided excellent recovery (101 to 102%). A median peak concentration of 190 (range, 185 to 231) g/ml was reached at 2 h (2 to 3 h) posttreatment. A naive pooled noncompartmental PK analysis estimated a mean area under the plasma concentration-versus-time curve (AUC) of 9,303 g h/ml (7,039.2 to 11,908.5 g h/ml) and a half-life of 38.7 h (20 to 64.6 h). Thus, the OZ418 level in plasma remained well above its in vitro 50% inhibitory concentrations (IC 50 s) of 27.4 g/ml (adult S. mansoni worms at 72 h) for at least 75 h. Consistently, OZ418 degraded little in plasma at 37°C (<20% in 121 h) and weakly inhibited cytochrome P450 (CYP450) metabolism (IC 50 of 37 to 144 M). Our results provide a first insight into the disposition of OZ418, paving the way for further studies of its biological fate and effect.A dult trematodes of the genus Schistosoma parasitize blood vessels of the intestine (e.g., Schistosoma mansoni and S. japonicum) and bladder (S. haematobium), causing a chronic condition known as schistosomiasis (1). Being one of the major neglected tropical diseases, schistosomiasis affects over 200 million people and leads to chronic morbidity and, in some cases, mortality (1-5). Moreover, almost 800 million people, mostly in rural sub-Saharan Africa, are estimated to be at risk for Schistosoma infection (6). No vaccine is yet available, and changing human behavior and eliminating the intermediate host (snail) remain challenging (7-9). Thus, the current strategy relies on praziquantel for the treatment and control of schistosomiasis (10-12). This drug is safe, relatively inexpensive, and easy to distribute (13, 14). However, it lacks efficacy against developing juvenile stages of Schistosoma, and its widespread use raises grave concerns about emerging resistance (15)(16)(17)(18)(19)(20). In addition, praziquantel's mechanism of action still requires further elucidation to intelligently design active derivatives (21-26). Therefore, new antischistosomal pharmacophores have been greatly sought after in recent years (10,27,28).Inspired by the peroxide pharmacophore of the artem...