Effect of multidrug resistance modulators on the activity of ivermectin and moxidectin against selected strains of Haemonchus contortus infective larvae

Nematode parasites have shown resistance to the anthelmintics, ivermectin and moxidectin, and there is evidence that the over-expression of parasite P-glycoprotein (P-gp) may account, at least in part, for resistance to ivermectin. The objective of this study was to evaluate whether the multidrug resistance (MDR) modulators, verapamil, CL 347.099 (an analog of verapamil) and cyclosporin A, would enhance the efficacy of ivermectin and moxidectin against selected strains of Haemonchus contortus using an in vitro larval migration assay. The modulators had no effects on the number of migrating larvae when used alone. Ivermectin and moxidectin showed a significant (P<0.05) increase in its efficacy by 52.8 and 58.5 per cent respectively, when used in association with verapamil against a moxidectin-selected strain. CL 347,099 also increased significantly (P<0.05) the ivermectin and moxidectin efficacy by 24.2 and 40.0 per cent respectively, against an ivermectin-selected strain and by 40.0 and 75.6 per cent respectively, against an moxidectin-selected strain. At the concentrations tested cyclosporin A showed a variable effect on increasing the efficacy of the anthelmintics against the susceptible and resistant strains

Reduced capacity of peritoneal exudate cells for oxidative killing of Schistosoma mansoni schistosomula

Peritoneal exudate cells from mice infected with Schistosoma mansoni (S-PEC) can kill schistosomula in vitro in the presence of immune serum. S-PEC produce a low level of respiratory burst, and schistosomula mortality in their presence is not reduced when exogenous antioxidants are added, suggesting that with S-PEC, oxidative killing is not important. Hydrogen peroxide (H2O2) and superoxide production by S-PEC, and cells from BCG and thioglycollate (THGL) injected non-infected mice, non-specifically stimulated with opsonized zymosan, were measured. Levels of H2O2 produced by S-PEC were significantly lower than BCG or THGL PEC, and were below the H2O2 threshold for schistosomula killing. This resulted in lower levels of cell-mediated killing of schistosomula in vitro by S-PEC than by BCG or THGL PEC. Superoxide levels, however, were similar between the three cell populations. The efficiency of PEC to kill schistosomules in vitro correlated with H2O2 rather than superoxide levels. The lower tolerance of schistosomula, compared to adult S. mansoni to GSH depleting agents increases their sensitivity to oxidative attack and resulted in higher levels of cell-mediated killing in vitro.