Effectiveness of synthetic trioxolane OZ78 against Schistosoma japonicum in mice and rabbits

Abstract

Antischistosomal activities of a synthetic peroxide OZ78 (an ozonide carboxylic acid) against Schistosoma japonicum have been studied in mice and rabbits. Among 132 mice used, 30 of them were infected with 80-100 S. japonicum cercariae for collection of juvenile and adult schistosomes applied in in vitro tests. The remaining 102 mice were infected with 40 schistosome cercariae used for experimental treatment. Other 13 rabbits infected each with 200 schistosome cercariae were treated orally with OZ78 42 days post-infection. Most treated mice and rabbits were sacrificed 4 weeks post-treatment to collect residual schistosomes for evaluation of the drug efficacy. OZ78 and its sodium salt (OZ78-Na salt) 10-60 μg/mL alone exhibited no in vitro effect against day 14, day 21 schistosomula, and day 35 adult schistosomes. But OZ78 and OZ78-Na salt 10 and 20 μg/mL together with hemin 80 μg/mL showed decrease in worm motor activity and severe damage to the worm tegument and intestine, and all worms died within 3 days post-incubation. After infected mice were treated orally with OZ78 at a single dose of 400 mg/kg for 1 day, 34.9% of the worms shifted to the liver. Three and 7 days post-treatment, 100% of the worms were recovered from the liver. Fourteen days post-treatment, 92.3% of the worms still remained in the liver and 7.7% of the worms returned back to the mesenteric veins. Male and female worms shifted to the liver revealed in apparent shrinkage, degeneration of worm body, depigmentation in gut, and disappearance of ova in the uterus of some female worms. Meanwhile, dead worm and dead worm fragments were found in the liver tissues. In mice infected with various stages of schistosomes and treated orally with single OZ78 400 mg/kg, moderate or potential effect of the drug against day 0 (3-h-old worm), day 7, day 14, and day 21 juvenile worms and day 28, day 35 as well as day 42 adult worms were observed, the differences of total or female worm burdens between each treated group and control group were statistically significant (P < 0.01 or P < 0.05). Among the various stages of juveniles, day 7 worms were more susceptible to OZ78 with worm reduction of 83.8%, while the effect of OZ78 against day 28 to day 42 adult worms were similar. Finally, rabbits infected with adult schistosomes and treated with OZ78 at a single dose of 45 mg/kg or a daily dose of 35 mg/kg for three consecutive days resulted in significantly lower total and female worm burdens in comparison with that of control (P < 0.05) with total and female worm reductions of 84.1% and 84.7% as well as 74.3% and 77.4%, respectively. The results demonstrate that OZ78 possesses effect against both juvenile and adult S. japonicum in mouse model, and also shows effect against adult schistosomes in rabbits.

Elimination of Schistosoma mansoni in infected mice by slow release of artemisone

“…Artemisinin derivatives (Araujo et al., 1991, del Villar et al., 2012, Saeed et al., 2016; Wikipedia, 2016) and artemisinin analogs-synthetic peroxides e.g. ozonides and trioxolanes (Keiser et al., 2012; Xiao et al., 2012) have been proposed as alternative or complementary drugs against schistosomes. Artemisinins are widely used against malaria wherein their mechanism of action is generally accepted to involve activation by heme or non-heme iron to generate cytotoxic carbon radicals that alkylate vital intraparastic molecules (Klonis et al., 2013).…”

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

“…SA4 and SA5 in the supplemental material), our preliminary data do not allow us to attribute any statistical significance to it. Interestingly, the peroxide moiety is essential for the antiparasitic activity of synthetic peroxides, yet the effect of iron sources on their in vitro activity varies widely (35,40,68). Thus, an additional iron-independent mechanism of action remains an open possibility for this type of compound.…”

“…Most importantly, they often offer improved bioavailability, pharmacokinetic (PK) properties, and antiparasitic activity (29)(30)(31). The artemisinins and ozonides have also shown promising efficacy against several parasitic worms, including schistosomes (27,(32)(33)(34)(35)(36)(37)(38)(39)(40). In more detail, the first screening of seven structurally diverse synthetic ozonides identified OZ288 as a possible antischistosomal compound.…”

“…More specifically, hemoglobin-derived iron(II) reduces the peroxide bond of the drug and thereby converts it into radicals that can attack the parasite by alkylation (47)(48)(49). Certain ozonides, however, have been reported to act against S. mansoni and S. japonicum in the absence of hemin in vitro, indicating a possible iron-independent pathway (35,39,40).…”

“…Besides OZ418, an acid substituent is also present in another synthetic ozonide with strong trematocidal activity, OZ78 (33,50). Although OZ78 has failed to affect adult S. mansoni in mice (35), it has shown a significant effect against both juvenile and adult S. mansoni in hamsters (35) as well as juvenile and adult S. japonicum in hamsters (36) and mice (40) and adult S. japonicum in rabbits (40). The role of acid functionality is not yet fully clear, but it might be an advantage in the low-pH environment of the parasite gut (38).…”