Results of the sellekchem hepatic shift experiments are used as an additional criterion for evaluating antischistosomal drugs since this test shows how quickly the forced dislodgement of worms occurs . For each experiment, groups of 5�C10 untreated mice served as controls. At 21 days post-treatment, animals were killed by the CO2 method and dissected, and worms were sexed and counted as described elsewhere . In vivo experiments with S. mansoni were carried out in duplicates. The results from the second set of experiment are summarized in Supporting Tables S1, S2, and S3. In vivo studies with S. japonicum Mice were infected percutaneously with ~40 S. japonicum cercariae each. To investigate the dose-response relationship of mefloquine against juvenile and adult S.
japonicum, single 25�C400 mg/kg oral doses were given to mice 14 days (pre-patent infection) and 35 days (patent infection) post-infection. To assess the efficacy of mefloquine against different stages of S. japonicum, mice were treated with a single oral dose of 400 mg/kg mefloquine 2 days or 1 day before infection, 3 hours after infection, and at days 3, 7, 14, 21, 28 and 35 post-infection. In each experiment, infected but untreated mice served as controls. Twenty-one days post-treatment, mice were killed and the worms recovered from the hepatic and portomesenteric veins by the perfusion technique . To study the hepatic shift in adult S. japonicum, groups of mice were treated with 400 mg/kg mefloquine 35 days post-infection, and the worm distribution was analyzed on days 1, 3, 7, and 14 post-treatment.
Statistical analysis For statistical analysis we used version 2.4.5 of the Statsdirect statistical software package (Cheshire, United Kingdom). The Kruskal-Wallis (KW) test, which compares the medians of the responses between the treatment and control groups, was used. A difference in median was considered to be significant at a significance level of 5%. Results Effect of selected antimalarials on S. mansoni harbored in mice The in vivo antischistosomal efficacy of 11 antimalarial drugs is summarized in Tables 1 and and2.2. Drugs were administered orally at a single dose of 400 mg/kg to mice harboring adult S. mansoni, and worm burden reductions, including changes in worm distributions, were assessed. Amodiaquine, atovaquone, lumefantrine, pyrimethamine, pyronaridine, sulfadoxine, and sulfamethoxypyrazine showed no antischistosomal activity.
Quinine and halofantrine resulted in total and female worm burden reductions ranging between 51.7% and 74.9% and changes in the worm distribution. The highest activity (total and female worm burden reduction of 77.3% and 100%, respectively) was observed with GSK-3 a single dose of mefloquine (400 mg/kg), which was statistically significant (p<0.05). The chemical structures of the four aminoalcohols quinine, halofantrine, lumefantrine, and mefloquine are shown in Figure 1.