Closantel plasma and milk disposition in dairy goats: assessment of drug residues in cheese and ricotta.

Closantel (CLS) is currently used in programs for the strategic control of gastrointestinal nematodes. CLS is extralabel used in different dairy goat production systems. From available data in dairy cows, it can be concluded that residues of CLS persist in milk. The current work evaluated the concentration profiles of CLS in plasma and milk from lactating orally treated dairy goats to assess the residues pattern in dairy products such as cheese and ricotta. Six (6) female Saanen dairy goats were treated orally with CLS administered at 10 mg/kg. Blood and milk samples were collected between 0 and 36 days post-treatment. The whole milk production was collected at 1, 4, 7, and 10 days post-treatment to produce soft cheese and ricotta. CLS concentrations in plasma, milk, cheese, whey, and ricotta were determined by HPLC. The concentrations of CLS measured in plasma were higher than those measured in milk at all sampling times. However, the calculated withdrawal time for CLS in milk was between 39 and 43 days postadministration to dairy goats. CLS residual concentrations in cheese (between 0.93 and 1.8 µg/g) were higher than those measured in the milk used for its production. CLS concentrations in ricotta were sixfold higher than those in the milk and 20-fold higher than those in the whey used for its production. The persistent and high residual concentrations of CLS in the milk and in the cheese and ricotta should be seriously considered before issuing any recommendation on the extralabel use of CLS in dairy goat farms.

Albendazole failure to control resistant nematodes in lambs: lack of effect of fasting-induced improvement on drug absorption.

Enhanced plasma availability of albendazole sulphoxide (ABZSO), the active metabolite of albendazole (ABZ), has been described in feed-restricted sheep. The aim of the present work was to determine if the absorption-related pharmacokinetic changes derived from fasting animals prior to drug treatment would modify the clinical efficacy of ABZ against resistant gastrointestinal nematodes in lambs. Forty Corriedale lambs, naturally infected with resistant gastrointestinal nematodes, were divided into 4 groups. Controls were fed ad libitum and did not receive any drug treatment. Treated animals were fed ad libitum up to 30 min prior to treatment with ABZ (3.8 mg/kg) by the intraruminal route. The control (fasted) animals were not fed during the 24-hr period prior to the start of the experiment and did not receive any drug treatment. A second treated group of animals were fasted 24 hr prior to the treatment with ABZ, as previously described for the fed-treated group. Blood samples were collected over a period of 72 hr post-treatment from 6 animals in each treated group. Plasma samples were analyzed by high performance liquid chromatography. The pharmacokinetic parameters were statistically compared using parametric statistical tests. The estimation of the efficacy of the different treatments was performed by the fecal egg count reduction test (FECRT). Additionally, 4 animals randomly chosen from the control-fed and treated groups were killed 13 days post-treatment to evaluate the efficacy against different adult nematode parasites. The results were statistically compared by parametric and non-parametric tests. Significantly (P < 0.05) higher Cmax and AUC values were observed for both the ABZSO and ABZ-sulphone (ABZSO(2)) metabolites in the fasted compared to the fed animals. These kinetic results may be due to a fasting-induced delay in the GI transit time which increases ABZ dissolution and GI absorption. However, a poor ABZ efficacy (measured as FECRT), compatible with a high degree of nematode resistance, was obtained in both fed (48%) and fasted (49%) animals. Haemonchus contortus and Trichostrongylus colubriformis appeared as the more reluctant species with respect to ABZ treatment. The efficacy against H. contortus ranged between 37 (fed) and 54% (fasted) and against T. colubriformis between 0% (fed) and 16% (fasted). Under these experimental conditions, the fasting-induced improvement on ABZ systemic availability (>60%) did not improve its activity against nematodes with a high degree of resistance. However, the data described here for a highly resistant nematode population should not discourage the use of fasting as a practical and well-proven management tool for parasite control in ruminants.

Clinical efficacy assessment of the albendazole-ivermectin combination in lambs parasitized with resistant nematodes.

Combination of anthelmintic drugs from different chemical groups has been proposed as alternative parasite control strategies where failure of individual drugs is documented. The main goal of the current trial was to compare the clinical anthelmintic efficacy of albendazole (ABZ) and ivermectin (IVM) given either separately or co-administered to lambs naturally infected with gastrointestinal nematodes resistant to both molecules. Seventy (70) Corriedale lambs naturally infected with multiple resistant gastrointestinal nematodes were involved in the efficacy trial: the animals were allocated into 7 experimental groups (n=10) and treated with either ABZ intravenously (iv) (ABZ(IV)), IVM(IV), ABZ(IV)+IVM(IV), ABZ intraruminally (ir) (ABZ(IR)), IVM subcutaneously (sc) (IVM(SC)) and ABZ(IR)+IVM(SC) or kept as untreated controls. The indirect estimation of the efficacy of the different treatments was performed by the faecal egg count reduction test (FECRT). Additionally, four animals randomly chosen from the untreated control and ABZ(IV,) IVM(IV) and ABZ(IV)+IVM(IV) experimental groups were sacrificed 15 days post-treatment to evaluate the efficacy against different adult resistant nematode parasites. The results were statistically compared by a non-parametric ANOVA (Kruskal-Wallis test). The following egg output reduction values were obtained: 73.4% (ABZ(IV)), 79.0% (IVM(IV)), 91.9% (ABZ(IV)+IVM(IV)), 43.5% (ABZ(IR)), 79.8% (IVM(SC)) and 70.8% (ABZ(IR)+IVM(SC)). The efficacy against Haemonchus spp. was 95.1 (ABZ(IV)), 99.3 (IVM(IV)) and 99.9% (ABZ(IV)+IVM(IV)), while the efficacy against Trichostrongylus colubriformis for the same treatment groups was 79.6, 100 and 99.9%. The data obtained on the assessment of the ABZ-IVM combination indicates that no potentiation synergism is observed. This work is complementary to a parallel study that demonstrated the lack of negative pharmacokinetic interactions between the two anthelmintics acting by different mode of action. Thus, an additive effect may be achieved against nematodes resistant to both compounds. Further work is required to understand the implications of potential pharmacokinetic/pharmacodynamic interactions between anthelmintics before drug combined formulations are developed to be introduced into the pharmaceutical market.

Evaluation of the interaction between ivermectin and albendazole following their combined use in lambs.

Mixtures of drugs from different chemical families have been proposed as a valid strategy to delay the development of anthelmintic resistance. The current work summarizes the outcome of the evaluation of the plasma disposition kinetics of albendazole (ABZ) and ivermectin (IVM) administered either alone or co-administered to lambs infected with gastrointestinal (GI) nematodes resistant to both anthelmintic molecules. Thirty six (36) Corriedale lambs naturally infected with multiple resistant GI nematodes were allocated into six treatment groups: (a) ABZ intravenous (ABZ(IV)); (b) IVM(IV); (c) ABZ(IV) + IVM(IV); (d) ABZ intraruminal (IR); (e) IVM subcutaneous (SC) and (f) ABZ(IR) + IVM(SC). Plasma samples were collected over 15 days post-treatment and analysed by HPLC. The estimated pharmacokinetic (PK) parameters were statistically compared using parametric and non-parametric statistical tests. The presence of IVM did not affect the plasma disposition kinetics of ABZ and its metabolites after the i.v. administration. However, the ABZ sulphoxide (ABZSO) area under the concentration vs. time curve (AUC) was significantly lower (P < 0.01) after the intraruminal (i.r.) administration of ABZ alone compared to that obtained for the combined treatment with IVM [subcutaneous (s.c.) injection]. The IVM plasma AUC obtained after its i.v. co-administration with ABZ was 88% higher (P < 0.05) compared to the treatment with IVM alone. Any marked difference on IVM PK parameters was observed between the treatments ABZ + IVM and IVM alone injected subcutaneously. The data obtained here indicate that the co-administration of ABZ and IVM does not induce an adverse kinetic interaction. This type of pharmacology-based evaluation of drug interactions is becoming highly relevant as drug combinations are now widely used as an alternative to control resistant helminth parasites in livestock.