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1The experiments described here were designed to characterize the status of 2 susceptibility/resistance to albendazole (ABZ) and triclabendazole (TCBZ) of a 3Fasciola hepatica isolate (named CEDIVE isolate) recovered from infected sheep 4 from in Gualeguay (Argentina) and maintained under laboratory conditions. Two 5 separate clinical efficacy experiments were performed. Experiment 1: Sheep 6 artificially infected with the CEDIVE isolate were randomly distributed into an 7 untreated control and an ABZ (7.5 mg/kg) treated groups (n= 4 each). The systemic 8 exposure of ABZ metabolites was assessed in those ABZ-treated infected animals. 9Additionally, an untreated control group and a TCBZ (10 mg/kg) treated group was 10 included in Experiment 2 (n=4 each). The fluckicidal efficacy of ABZ and TCBZ was 11 assessed by comparison of the number of flukes recovered from untreated and treated 12 sheep at 15 days post-treatment. The efficacy against the CEDIVE isolate of F. 13 hepatica was 29% (ABZ) and 100 % (TCBZ). The plasma drug exposure (expressed 14 as AUC and Cmax) observed in the ABZ treated animals (Experiment 1), was in 15 agreement with data obtained in previous studies, which indicate that the low ABZ 16 efficacy was not related to the quality of the pharmaceutical product and/or to a low 17 systemic availability of the active drug/metabolite. The results reported here, clearly 18show that the CEDIVE isolate of F. hepatica behaves as resistant to ABZ and 19 susceptible to TCBZ. 20 21

The goals were to determine the ivermectin (IVM) plasma pharmacokinetics, tissue and egg residue profiles, and in vitro metabolism in laying hens. Experiments conducted were (1) 8 hens were intravenously treated with IVM and blood samples taken; (2) 88 hens were treated with IVM administered daily in water (5 days) (40 were kept and their daily eggs collected; 48 were sacrificed in groups (n = 8) at different times and tissue samples taken and analyzed); (3) IVM biotransformation was studied in liver microsomes. Pharmacokinetic parameters were AUC = 85.1 ng·day/mL, Vdss = 4.43 L/kg, and T1/2el = 1.73 days. Low IVM tissue residues were quantified with the highest measured in liver and skin+fat. IVM residues were not found in egg white, but significant amounts were quantified in yolk. Residues measured in eggs were greater than some MRL values, suggesting that a withdrawal period would be necessary for eggs after IVM use in laying hens.

The main goal of the current work was to develop and validate an in vitro fluke egg hatch test, as a method for the detection of albendazole (ABZ) resistance in the liver fluke, Fasciola hepatica. Fluke eggs (200/ml, n= 5) from six different isolates were used in the current experimental work. They were obtained from different geographical locations and named Cullompton (UK), CEDIVE (Chascomus, Argentina), INTA-Bariloche (Bariloche, Argentina), Rubino (Uruguay), Cajamarca (Perú) and Río Chico (Catamarca, Argentina). The fluke eggs were incubated (25 °C) for a 12-h period in the presence of either ABZ or its sulphoxide metabolite (ABZ.SO) (5, 0.5 or 0.05 nmol/ml). Untreated eggs were incubated as a control. Incubated eggs (with or without drug present) were kept in darkness at 25 °C for 15 days. Afterwards, the trematode eggs were exposed to daylight over a 2-h period. Hatched and unhatched eggs were evaluated using an optical microscope, and the ovicidal activity was assessed for each fluke isolate. A very low ovicidal activity ( ≤ 13.4%) was observed in the ABZ-resistant CEDIVE isolate for both ABZ and ABZ.SO. Conversely, in the INTA-Bariloche and Río Chico isolates, which are suspected to be susceptible to ABZ, ovicidal activities ≥ 70.3% were observed after incubation with ABZ at the lowest concentration tested (0.05 nmol/ml). This finding correlates with that previously described for the ABZ-susceptible Cullompton. Finally, the Cajamarca and Rubino isolates behaved as ABZ resistant, since no ovicidal activity was observed after eggs were incubated with ABZ at 0.5 nmol/ml. Considering the specific results obtained for each isolate under assessment, the egg hatch test described here may be a suitable method for detection of ABZ resistance in F. hepatica.

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