Production and metabolism studies on bovine trichostrongylosis

In this thesis the sequential development of naturally occurring bovine trichostrongylosis in the same animals was studied, for the first time, over a two year period. The species of gastro-intestinal trichostrongyle most frequently present were primarily Ostertagia ostertagi and Cooperia oncophora; a few Trichostrongylus axei were also recorded. In a control group of 16 calves, overwintered larvae of O. ostertagi and C. oncophora were acquired in the spring of their first grazing season. The eggs resulting from these infections gave rise to another generation of larvae on the pastures by August, which was sufficient in number to cause the type I disease, characterised by loss of appetite, diarrhoea and weight loss. One animal was destroyed in extremis just prior to the type I disease, clinical signs of parasitic bronchitis occurred namely, increased respiratory rate and coughing necessitating treatment with diethylcarbamazine and then levamisole. At housing in October, five calves were slaughtered and the post-mortem worm burdens consisted almost entirely of early 4th stage larvae of O. ostertagi and C. oncophora, which were arrested in development. Following housing in October, the animals were clinically normal during the so-called pre-type II phase, until late February and early March when some reduction in appetite was noted which was followed by clinical diarrhoea and weight loss in April and May in the so called type II disease. During the second grazing season, the animals acquired a solid immunity to C. oncophora and a good immunity to O. ostertagi and this was reflected in the low numbers of eggs in the faeces, relatively low numbers of larvae an the pasture and low worm burdens at final slaughter two months after housing in October. A second group of 16 calves, which were grazed on immediately adjacent but separate fields, received a sustained release device containing the anthelmintic morantel tartrate, which was introduced by a special dosing gun into the rumen of each calf prior to grazing in the spring of each year. The boli were designed to release the drug over a 90-day period and their introduction prevented the build-up of larval infection on the pasture and the occurrence of the type I and the type II disease. The advantage in live weight gain alone over the two year period amounted to a mean of 33 kg over the controls. Furthermore, the introduction of the boli did not interfere with the acquisition of immunity in the second grazing season. Several biochemical parameters were monitored of which two, serum pepsinogen and gastrin levels, proved particularly interesting. All values of these parameters became markedly elevated when large numbers of parasites were actively developing to the adult stage i.e. during the type I and type II disease, but not during the pre-type II phase when the worm populations consisted mainly of arrested larval stages, or when the animals become immune. The single and combined linear relationship between pepsinogen, gastrin and numbers of developing and adult Ostertagia parasites was very highly significant. Although further information is necessary to define normal bovine plasma gastrin levels and the affecting factors, the results in this study suggest that the evaluation of plasma gastrin could be a useful adjunct to plasma pepsinogen as a combination diagnostic test for ostertagiasis, particularly when pepsinogen values may be only moderately elevated in Immune cattle under larval challenge. (Abstract shortened by ProQuest.)

Comparative tissue pharmacokinetics and efficacy of moxidectin, abamectin and ivermectin in lambs infected with resistant nematodes: Impact of drug treatments on parasite P-glycoprotein expression

AbstractThe high level of resistance to the macrocyclic lactones has encouraged the search for strategies to optimize their potential as antiparasitic agents. There is a need for pharmaco-parasitological studies addressing the kinetic-dynamic differences between various macrocyclic lactones under standardized in vivo conditions. The current work evaluated the relationship among systemic drug exposure, target tissue availabilities and the pattern of drug accumulation within resistant Haemonchus contortus for moxidectin, abamectin and ivermectin. Drug concentrations in plasma, target tissues and parasites were measured by high performance liquid chromatography. Additionally, the efficacy of the three molecules was evaluated in lambs infected with resistant nematodes by classical parasitological methods. Furthermore, the comparative determination of the level of expression of P-glycoprotein (P-gp2) in H. contortus recovered from lambs treated with each drug was performed by real time PCR. A longer persistence of moxidectin (P<0.05) concentrations in plasma was observed. The concentrations of the three compounds in the mucosal tissue and digestive contents were significant higher than those measured in plasma. Drug concentrations were in a range between 452ng/g (0.5day post-treatment) and 32ng/g (2days post-treatment) in the gastrointestinal (GI) contents (abomasal and intestinal). Concentrations of the three compounds in H. contortus were in a similar range to those observed in the abomasal contents (positive correlation P=0.0002). Lower moxidectin concentrations were recovered within adult H. contortus compared to abamectin and ivermectin at day 2 post-treatment. However, the efficacy against H. contortus was 20.1% (ivermectin), 39.7% (abamectin) and 89.6% (moxidectin). Only the ivermectin treatment induced an enhancement on the expression of P-gp2 in the recovered adult H. contortus, reaching higher values at 12 and 24h post-administration compared to control (untreated) worms. This comparative pharmacological evaluation of three of the most used macrocyclic lactones compounds provides new insights into the action of these drugs

Estrategias farmacológicas contra la resistencia a drogas antihelmínticas en ovinos: modulación in vivo de la glicoproteína-P en el huésped y en los parásitos resistentes

En los últimos años, un nuevo paradigma se ha incorporado al estudio farmacocinético de diversos grupos de drogas con la participación de diferentes transportadores celulares de membrana en los procesos de absorción, distribución tisular y excreción de compuestos farmacológicamente activos. De todos los transportadores celulares identificados, la glicoproteína-P (gp-P) ha sido la más estudiada. Si bien la gp-P fue inicialmente descripta por su sobreexpresión en células tumorales resistentes a múltiples drogas anticancerígenas, también se localiza en células normales de tejidos involucrados en los procesos de absorción, distribución, y excreción de fármacos (Ballent et al., 2005). Esta proteína actúa como una bomba de eflujo que es capaz de bombear una amplia gama de compuestos hacia el exterior celular por un proceso dependiente de energía. La localización específica en estos tejidos sugiere que la gp-P cumpliría un importante rol en la regulación del transporte de fármacos, modificando de este modo el comportamiento cinético y la biodisponibilidad de los mismos (Schinkel, 1997).Trabajo galardonado con el Premio Fundación Pérez Companc, versión 2011Academia Nacional de Agronomía y Veterinari

Estrategias farmacológicas contra la resistencia a drogas antihelmínticas en ovinos: modulación in vivo de la glicoproteína-P en el huésped y en los parásitos resistentes

En los últimos años, un nuevo paradigma se ha incorporado al estudio farmacocinético de diversos grupos de drogas con la participación de diferentes transportadores celulares de membrana en los procesos de absorción, distribución tisular y excreción de compuestos farmacológicamente activos. De todos los transportadores celulares identificados, la glicoproteína-P (gp-P) ha sido la más estudiada. Si bien la gp-P fue inicialmente descripta por su sobreexpresión en células tumorales resistentes a múltiples drogas anticancerígenas, también se localiza en células normales de tejidos involucrados en los procesos de absorción, distribución, y excreción de fármacos (Ballent et al., 2005). Esta proteína actúa como una bomba de eflujo que es capaz de bombear una amplia gama de compuestos hacia el exterior celular por un proceso dependiente de energía. La localización específica en estos tejidos sugiere que la gp-P cumpliría un importante rol en la regulación del transporte de fármacos, modificando de este modo el comportamiento cinético y la biodisponibilidad de los mismos (Schinkel, 1997).Trabajo galardonado con el Premio Fundación Pérez Companc, versión 2011Academia Nacional de Agronomía y Veterinari

Measurement of ivermectin concentrations in target worms and host gastrointestinal tissues: Influence of the route of administration on the activity against resistant Haemonchus contortus in lambs

The influence of the administration route on the relationship between efficacy and ivermectin concentration profiles achieved in the bloodstream, the gastrointestinal mucosal tissues/fluid contents and within a target abomasal parasite (Haemonchus contortus) was evaluated in lambs. Twenty-six (26) parasitized lambs were assigned into three experimental groups: untreated (control) and ivermectin treated by the subcutaneous and intraruminal route at 0.2. mg/kg. Blood samples were collected between 0 and 15. days post-treatment (plasma disposition study). Four animals from each group were sacrificed at day 3 post-treatment. Mucosa and content samples from abomasum and small intestine and adult specimens of H. contortus were collected. Drug concentrations were measured by HPLC. Individual fecal egg counts were evaluated at -1, 3 and 15. days post treatment. Post-mortem examination was done at day 15 post-treatment. Adult nematodes recovered from the digestive tract were counted and identified by species. Ivermectin plasma availability was higher (P< 0.05) after the subcutaneous administration (129. ng.d/ml) compared to the intraruminal treatment (58.4. ng.d/ml). However, ivermectin concentrations measured in the gastrointestinal contents were higher in lambs treated by the intraruminal route. The mean ivermectin concentrations achieved (3. days post-treatment) in the abomasal content were 143. ng/g (intraruminal) and 2.53. ng/g (subcutaneous). Ivermectin concentrations were 15-fold higher in H. contortus recovered from intraruminally treated lambs. Whereas the subcutaneous administration reduced the number of adult nematodes from 4376 to 1300, the number of adult nematodes after the treatment with ivermectin given by the intraruminal route was 206 (P< 0.05). The higher ivermectin concentrations achieved in the digestive tract shortly after the intraruminal treatment may account for the observed enhanced efficacy compared to the parenteral administration against parasites of reduced susceptibility.Fil: Lloberas, Maria Mercedes. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires Sur. Estación Experimental Agropecuaria Balcarce; ArgentinaFil: Alvarez, Luis Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Entrocasso, Carlos. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires Sur. Estación Experimental Agropecuaria Balcarce; ArgentinaFil: Virkel, Guillermo Leon. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Lanusse, Carlos Edmundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Lifschitz, Adrian Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentin

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 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.Fil: Alvarez, L.. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; ArgentinaFil: Entrocasso, C.. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; ArgentinaFil: Lifschitz, Adrian Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; ArgentinaFil: Manazza, J.. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; ArgentinaFil: Ceballos, Laura. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; ArgentinaFil: Borda, B.. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; ArgentinaFil: Lanusse, Carlos Edmundo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; Argentin

Moxidectin remains efficacious against ivermectin-resistant Haemonchus contortus: comparative pharmacological assessment of single and double dose-responses

Although the macrocyclic lactones ivermectin (IVM) and moxidectin (MXD) share some pharmacological properties, a differential pattern of efficacy against resistant nematodes has been described (Vickers et al., 2001). Enhanced drug concentration within the worm and improved efficacy against resistant Haemonchus contortus have been recently reported after the intraruminal administration of IVM compared to the subcutaneous treatment (Lloberas et al., 2012). This work aimed to assess the relationship between anthelmintic activity and host tissue/parasite exposure for IVM and MXD in lambs naturally-infected with resistant H. contortus. The influence of a 2-fold dosage on the drug concentrations achieved at the host (bloodstream, gastrointestinal content/tissues) and within H. contortus were simultaneously evaluated with the clinical efficacy. Forty eight (48) naturally parasitised lambs were assigned into four (4) experimental groups and intraruminally treated with either IVM or MXD at 0.2 and 0.4 mg/kg. Blood samples were collected over 14 days post-treatment. Parasitological post-mortem examination was done at day 15 post-treatment. The recovered worms were identified by species and counted. Additionally, mucosal and fluid content samples and adult specimens of H. contortus were recovered at day 1 post-treatment. IVM and MXD were measured by HPLC. Both IVM and MXD concentration profiles measured within H. contortus reflected those observed in the abomasal contents. In spite of the high concentrations recovered from the abomasal content and within the worm, IVM completely failed to control H. contortus (0% efficacy) at both dose rates. Oppositely, MXD efficacy against this IVM-resistant H. contortus strain was 94.2 (therapeutic dosage) and 99.1% (double dose). The improved drug exposure (target worm) achieved after the oral/intraruminal treatment compared to the subcutaneous injection (Lloberas et al., 2012), as well, as the advantageous MXD efficacy performance observed at twice the dose should be seriously considered to optimise nematode control before a complete therapeutic failure is observed.Fil: Lifschitz, Adrian Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Lloberas, Maria Mercedes. Instituto Nacional de Tecnologia Agropecuaria. Centro Regional Buenos Aires Sur. Estacion Experimental Agropecuaria Balcarce. Agencia de Extension Rural Tandil.; ArgentinaFil: Alvarez, Luis Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Entrocasso, Carlos. Instituto Nacional de Tecnologia Agropecuaria. Centro Regional Buenos Aires Sur. Estacion Experimental Agropecuaria Balcarce. Agencia de Extension Rural Tandil.; ArgentinaFil: Ballent, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Virkel, Guillermo Leon. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Luque, Sonia Elisabet. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; ArgentinaFil: Lanusse, Carlos Edmundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil. Centro de Investigación Veterinaria de Tandil. Universidad Nacional del Centro de la Provincia de Buenos Aires. Centro de Investigación Veterinaria de Tandil. Provincia de Buenos Aires. Gobernación. Comision de Investigaciones Científicas. Centro de Investigación Veterinaria de Tandil; Argentina24º International Conference of the World Association for the Advancement of Veterinary ParasitologyPerthAustraliaWorld Association for the Advancement of Veterinary Parasitolog

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) (ABZIV), IVMIV, ABZIV + IVMIV, ABZ intraruminally (ir) (ABZIR), IVM subcutaneously (sc) (IVMSC) and ABZIR + IVMSC 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 ABZIV, IVMIV and ABZIV + IVMIV 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% (ABZIV), 79.0% (IVMIV), 91.9% (ABZIV + IVMIV), 43.5% (ABZIR), 79.8% (IVMSC) and 70.8% (ABZIR + IVMSC). The efficacy against Haemonchus spp. was 95.1 (ABZIV), 99.3 (IVMIV) and 99.9% (ABZIV + IVMIV), 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.Fil: Entrocasso, Carlos. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires Sur. Estación Experimental Agropecuaria Balcarce. Área de Investigación en Producción y Sanidad Animal; ArgentinaFil: Alvarez, Luis Ignacio. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Manazza, Jorge Alberto. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires Sur. Estación Experimental Agropecuaria Balcarce. Área de Investigación en Producción y Sanidad Animal; ArgentinaFil: Lifschitz, Adrian Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias; ArgentinaFil: Borda, Bernardino. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires Sur. Estación Experimental Agropecuaria Balcarce. Área de Investigación en Producción y Sanidad Animal; ArgentinaFil: Virkel, Guillermo Leon. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias; ArgentinaFil: Mottier, Maria de Lourdes. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias; ArgentinaFil: Lanusse, Carlos Edmundo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias; Argentin