233 research outputs found
Fenbendazole and triclabendazole effects on CYP1A1/1A2 and FMO1/3 mRNAs in cattle liver slices: preliminary results
No full textBackground. Fenbendazole (FBZ) and triclabendazole (TCBZ) are benzimidazole drugs (BZDs) widely used in veterinary practice as anthelmintics. Members of cytochrome P450 (CYP) and flavin monooxygenase (FMO) superfamilies of drug metabolizing enzymes are primarily responsible of their biotransformation1. The xenobiotic-dependent up-regulation of CYPs is well documented, while FMOs are generally considered not inducible2. In the present study, the effect of FBZ and TCBZ (alone or in combination) on CYP1A1/2 and FMO1/3 mRNA levels were measured on precision-cut bovine liver slices (bLS).
Methods. Precision-cut bLS from 6 male cattle were obtained according to Maté et al3. Following the fine-tuning of an absolute quantification protocol for target genes4, bLS were incubated for 0, 6 and 12 h with FBZ and TCBZ (50 μM), alone or in combination. β-naphthoflavone (βNF, 25 μM) was used as positive control to confirm gene induction. Target gene mRNA levels were measured by qPCR. The TATA Box binding protein and ribosomal protein lateral stalk subunit P0/β-actin were used as internal control genes to normalize FBZ/TCBZ and βNF data, respectively.
Results. At T0, CYP1A2 mRNA levels were 25-fold higher than CYP1A1; however, FMO1 and 3 were equally represented. βNF up-regulated CYP1A1 (P<0.05; 4-fold vs control) after 6 h of incubation, while increasing amounts (P<0.05) of CYP1A2, FMO1/3 mRNAs were noticed after 12 h (4-, 2.5- and 3.5-fold vs control, respectively). Concerning BZDs, FBZ increased CYP1A1/2 mRNAs (P<0.05) after 12 h of incubation, whereas TCBZ up-regulated only FMO3 (P<0.05) and after 6 h. No transcriptional effect was ever noticed following bLS exposure to BZDs combination.
Conclusion. Likewise to humans, bLS appear to be a reliable model to study CYP1A induction by NF and other potential aryl hydrocarbon receptor agonists. Meanwhile, for the first time we proved cattle FMO1-3 up-regulation by NF. About BZDs, FBZ and TCBZ were shown to affect CYP1A1/2 and FMO3 gene expression. Confirmatory studies on CYP1A and FMOs catalytic activities are actually underway
Macrocyclic lactones: endectocide compounds
No full textGeneral pharmacology: avermectins and milbemycinsMechanism of action: ecto-endoparasiticidal activity pharmacokinetics - exchange between bloodstream and target tissues - metabolism. Bile and intestinal excretion. Involvement of drug transport systems. Pharmacokinetic-pharmacodynamic relationship. Therapeutic uses: animal species-specific considerations. Resistance available pharmaceutical preparations. Drug and host-related factors affecting pharmacokinetics and efficacy in ruminants.Tissue residues. Withdrawal times. Safety and toxicity. Ecotoxicological impact. Concluding remarks.Fil: 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: Imperiale, Fernanda Andrea. 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
Spatiotemporal heterogeneity of Rhipicephalus microplus resistance to chemical acaricides at intra-farm level: A case study using ivermectin
No full textThe aim of this work was to analyse the spatiotemporal heterogeneity of Rhipicephalus microplus (Canestrini, 1888) (Acari: Ixodidae) resistance to chemical acaricides at intra-farm level under different environmental (favourable and unfavourable areas for tick development) and management (different schemes of acaricides applications) conditions using ivermectin as a model. The in vitro larval immersion test (LIT) was used to determine quantitatively the levels of resistance to ivermectin in the different populations and subpopulations of R. microplus analysed. In the first case study, differences in resistance levels among tick samples within the same paddock across time and among tick samples from different paddocks were recorded. These results stress the importance of taking successive samples so that they represent the spatial and temporal variabilities in the levels of resistance that can occur within the same farm. In a second case study, the evolution of resistance in R. microplus subpopulations subjected to strategic and threshold control methods based on the application of three annual treatments with alternation of chemical groups was compared. No changes in resistance/susceptibility status were observed in both tick subpopulations. These results show that the application of a particular drug once a year within a scheme of alternation with other chemical groups could be an appropriate strategy to delay the development of resistance. Data of the third case study showed that environmental constraints is not only a key modulator of R. microplus abundance but could also affect the evolution of resistance in the tick populations. The decreasing trend of LC50 values in the tick subpopulation not exposed to chemical treatments but also in that subpopulation exposed to three annual chemical treatments under unfavourable environmental conditions allow us to hypothesise that environmental constraints can modify the levels of resistance in a tick population because it can constitute a stronger selection factor than the treatments themselves.Instituto Nacional de Tecnología Agropecuaria (INTA), Asociación Cooperadora INTA Rafaela y Secretaría de Innovación, Ciencia y Tecnología (Proyectos de Redes Federales de Alto Impacto: REDGARR 100390265)EEA RafaelaFil: Morel, Nicolas. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Rafaela. Instituto de Investigación de la Cadena Láctea (IdICaL); ArgentinaFil: Morel, Nicolas. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Instituto de Investigación de la Cadena Láctea (IdICaL); ArgentinaFil: Torrents, Jorgelina. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Rafaela. Instituto de Investigación de la Cadena Láctea (IdICaL); ArgentinaFil: Torrents, Jorgelina. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Instituto de Investigación de la Cadena Láctea (IdICaL); ArgentinaFil: Torrents, Jorgelina. Universidad Nacional del Litoral. Facultad de Ciencias Veterinarias; ArgentinaFil: Sarli, Macarena. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Rafaela. Instituto de Investigación de la Cadena Láctea (IdICaL); ArgentinaFil: Sarli, Macarena. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Instituto de Investigación de la Cadena Láctea (IdICaL); ArgentinaFil: Rossner, Maria Victoria. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Colonia Benitez; ArgentinaFil: Lifschitz, Adrian. Universidad Nacional del Centro de la Provincia de Buenos Aires (UNCPBA). Facultad de Ciencias Veterinarias; ArgentinaFil: Lifschitz, Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Centro de Investigación Veterinaria de Tandil (CIVETAN); ArgentinaFil: Lifschitz, Adrian. Universidad Nacional del Centro de la Provincia de Buenos Aires (UNCPBA). Centro de Investigación Veterinaria de Tandil (CIVETAN). Laboratorio de Farmacología; ArgentinaFil: Nava, Santiago. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Rafaela. Instituto de Investigación de la Cadena Láctea (IdICaL); ArgentinaFil: Nava, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Instituto de Investigación de la Cadena Láctea (IdICaL); Argentin
Gaining Insights Into the Pharmacology of Anthelmintics Using Haemonchus contortus as a Model Nematode
No full textProgress made in understanding pharmacokinetic behaviour and pharmacodynamic mechanisms of drug action/resistance has allowed deep insights into the pharmacology of the main chemical classes, including some of the few recently discovered anthelmintics. The integration of pharmaco-parasitological research approaches has contributed considerably to the optimization of drug activity, which is relevant to. preserve existing and novel active compounds for parasite control in livestock. A remarkable amount of pharmacology-based knowledge has been generated using the sheep abomasal nematode Haemonchus contortus as a model. Relevant fundamental information on the relationship among drug influx/efflux balance (accumulation), biotransformation/detoxification and pharmacological effects in parasitic nematodes for the most traditional anthelmintic chemical families has been obtained by exploiting the advantages of working with H. contortus under in vitro, ex vivo and in vivo experimental conditions. The scientific contributions to the pharmacology of anthelmintic drugs based on the use of H. contortus as a model nematode are summarized in the present chapter.Fil: 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: 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: 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
New recommendations for measuring collagen solubility
No full textThe heat-solubility of intramuscular collagen is usually conducted in 1/4 Ringer's solution at pH 7.4, despite this ionic strength and pH being inappropriate for post-rigor meat. The current work studied the percentage of soluble collagen and hydrothermal isometric tension characteristics of perimysial strips on bovine semitendinosus muscles in either 1/4 Ringer's solution, distilled water, PBS, or a solution of the same salt concentration as 1/4 Ringer's but at pH 5.6. Values of % soluble collagen were lower at pH 7.4 than 5.6. Increasing ionic strength reduced % soluble collagen. The maximum perimysial isometric tension was independent of the bathing medium, but the percent relaxation was higher at pH 7.4 than at pH 5.6, and increased with ionic strength of the media. It is recommended that future measurements of collagen solubility and tests on connective tissue components of post-rigor meat should be carried out in a solution of concentrations NaCl and KCl equivalent to those in 1/4 Ringer's, but at pH 5.6, a pH relevant to post-rigor meat.Fil: Latorre, Maria Emilia. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; 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; ArgentinaFil: Purslow, Peter. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Tecnologia y Calidad de los Alimentos; Argentin
Macrocyclic lactones and cellular transport-related drug interactions: A perspective from in vitro assays to nematode control in the field
No full textMacrocyclic lactones (MLs) are antiparasitic drugs used against endo-ectoparasites. Regarding the wide use of MLs in different species, it is likely that drug-drug interactions may occur after their co-administration with other compounds. A new paradigm was introduced in the study of the pharmacology of MLs during the last years since the interactions of MLs with ATP-binding cassete (ABC) transporters have been described. The current review article gives an update on the available information concerning drug-drug interactions involving the MLs. The basis of the methodological approaches used to evaluate transport interactions, and the impact of the pharmacology-based modulation of drug transport on the MLs disposition kinetics and clinical efficacy, are discussed in an integrated manner. A different number of in vitro and ex vivo methods have been reported to study the characterization of the interactions between MLs and ABC transporters. The production of the ABC transporters knockout mice has provided valuable in vivo tools to study this type of drug-drug interaction. In vivo trials performed in different species corroborated the effects of ABC transporter modulators on the pharmacokinetics behaviour of MLs. Important pharmacokinetic changes on plasma disposition of MLs have been observed when these compounds are co-administered with P-glycoprotein modulators. The modulation of the activity of P-glycoprotein was evaluated as a strategy not only to increase the systemic availability of MLs but also to improve their clinical efficacy. The understanding of the MLs interactions may supply relevant information to optimize their use in veterinary and human therapeutics.Fil: Lifschitz, Adrian Luis. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ballent, Mariana. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lanusse, Carlos Edmundo. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin
Parasitosis gastrointestinales en ovinos del sudeste bonaerense
No full textEstrategias de control farmacológico de las parasitosis gastrointestinales en un contexto de creciente avance de la resistencia antihelmíntica. Consideraciones epidemiológica y prácticas para su implementación.EEA BalcarceFil: Luque, Sonia. Actividad Privada; Argentina.Fil: Cardozo, Patricia. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Balcarce; Argentina.Fil: Lloberas, María Mercedes. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión de Investigaciones Científicas; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires; Argentina. Centro de Investigación Veterinaria de Tandil; Argentina.Fil: Lloberas, María Mercedes. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Balcarce; Argentina.Fil: Álvarez, Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión de Investigaciones Científicas; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires; Argentina. Centro de Investigación Veterinaria de Tandil; Argentina.Fil: Lifschitz, Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Centro de Investigaciones Veterinarias de Tandil (CIVETAN); ArgentinaFil: Lifschitz, Adrián. Universidad Nacional del Centro de la Provincia de Buenos Aires (UNICEN). Centro de Investigaciones Veterinarias de Tandil (CIVETAN); ArgentinaFil: Lifschitz, Adrián. Comisión de Investigaciones Científicas (CIC). Centro de Investigaciones Veterinarias de Tandil (CIVETAN); Argentin
Basic and clinical pharmacology contribution to extend anthelmintic molecules lifespan
No full textThe correct use of pharmacology-based information is critical to design successful strategies for the future of parasite control in livestock animals. Integrated pharmaco-parasitological research approaches have greatly contributed to optimize drug activity. In an attempt to manage drug resistance in helminths of ruminants, combinations of two or more anthelmintics are being used or promoted, based on the fact that individual worms may have a lower degree of resistance to a multiple component formulation, when each chemical has a different mode of action compared to that observed when a single compound is used. However, as emphasized in the current review, the occurrence of potential pharmacokinetic and/or pharmacodynamic interactions between drug components highlights the need for deeper and integrated research to identify the advantages or disadvantages associated with the use of combined drug preparations. This review article provides integrated pharmacokinetic/pharmacodynamic and clinical pharmacology information pertinent to preserve the traditional and modern active ingredients as practical tools for parasite control. Novel pharmacological data on derquantel and monepantel, as representatives of modern anthelmintics for use in livestock, is summarized here. The article also summarizes the pharmaco-parasitological knowledge considered critical to secure and/or extend the lifespan of the recently available novel molecules.Fil: 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; 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; Argentin
Evaluación cinético-dinámica in vivo e in vitro en Haemochus contortus resistente a lactonas macrocíclicas
No full textTesis para obtener el grado de Doctora en Ciencia Animal, de la Universidad Nacional del Centro de la Provincia de Buenos Aires, en 2018La parasitosis gastrointestinal continúa siendo una de las principales causas de pérdidas económicas en la producción pecuaria y dentro de ella, la haemonchosis es sin duda la enfermedad más patógena y la que mayores pérdidas genera en la producción ovina. El control de las parasitosis debiera consistir en diversas estrategias de manejo de los animales y las pasturas junto con la administración de antihelmínticos, luego del diagnóstico parasitológico y terapéutico adecuado. Sin embargo, en las últimas tres décadas el control se basó casi exclusivamente en el utilización masiva de drogas antihelmínticas de amplio espectro cada vez más eficaces y persistentes. El incremento de la resistencia antihelmíntica junto con las nuevas tendencias de producción orgánica y disminución de los residuos de drogas en los alimentos generó interés en el estudio de nuevas estrategias de control. En este contexto el presente trabajo de Tesis Doctoral abordó la resistencia antihelmíntica desde un enfoque integrador fármaco-parasitológico, cuyo objetivo fue estudiar la relación que existe entre las concentraciones de diferentes lactonas macrocíclicas en plasma, tejidos/fluidos de localización parasitaria del ovino y en el parásito “blanco” y la eficacia sobre Haemonchus contortus resistente. Para ello se dividió la Tesis en 3 secciones experimentales. En la Primera se realizó la caracterización in vivo de factores que afectan la relación entre concentraciones en el sitio de localización parasitaria, concentraciones en el parásito “blanco” (H. contortus) y eficacia antihelmíntica para diferentes lactonas macrocíclicas en corderos infestados con parásitos resistentes y bajo condiciones estandarizadas. Dentro de esta sección se relizaron 3 experimentos en donde se comparó la utilización de dos vías de administración (subcubtánea e intraruminal), las diferentes lactonas macrocíclicas (ivermectina-abamectina-moxidectina) y la duplicación de la dosis como estrategias para aumentar la eficacia antihelmíntica. Se encontró que si bien la disposición plasmática es mayor al utilizar la vía subcutánea, las concentraciones son mayores en los tejidos y contenidos del tracto gastrointestinal a los 2-3 días post-tratamiento por vía intraruminal y esto produce un efecto relevante cuando se trata de nematodos resitentes, de tal forma que la eficacia contra H. contortus fue un 40 % mayor al utilizar la vía intraruminal, coincidentemente con las mayores concentraciones de ivermectina halladas dentro del parásito. Esto demuestra que la incorporación de la droga al parásito por vía transcuticular es relevante para la eficacia clínica, aún para aquellos parásitos que son hematófagos. En el segundo experimento se encontró que a la dosis terapéutica, moxidectina fue más efectiva frente a nematodos resistentes a ivermectina. Las concentraciones de los 3 fármacos encontradas en los tejidos del tracto gastrointestinal durante los primeros 2 días post tratamiento es relevante para su acción sobre los nematodos resistentes. Sin embargo, a pesar de que moxidectina obtuvo las menores concentraciones acumuladas en los parásitos adultos, el total de parásitos recuperados (al día 2) post tratamiento y su eficacia antihelmíntica fue mayor que la de ivermectina y abamectina. En el tercer experimento, donde se comparó la eficacia y la acumulación de fármacos en los tejidos de los corderos y en el H. contortus, utilizando ivermectina y moxidectina a la dosis terapéutica y al doble de la dosis terapéutica, debido al extremo grado de resistencia, sólo la administración de doble dosis de moxidectina fue efectiva. En la Sección Experimental II, se caracterizó in vitro la actividad de las lactonas macrocíclicas contra H. contortus resistente, mediante el desarrollo del test de inhibición de motilidad larval utilizando estadios larvarios de H. contortus. Esta prueba resultó ser una prueba eficaz para establecer diferencias entre aislamientos susceptibles de resistentes. Sin embargo, es una prueba difícil de implementar para el diagnóstico de resistencia de rutina. También se desarrolló un método ex vivo, para caracterizar el ingreso del fármaco dentro de los parasitos adultos. El incremento de la exposición a ivermectina y moxidectina se reflejan como un incremento en la cantidad de droga recuperada en los H. contortus. En la Sección Experimental III se estudiaron los cambios génicos en H. contortus asociados al fenómeno de resistencia. Se validó una metodología para cuantificar la expresión de glicoproteína-P2 en aislamientos de H. contortus susceptibles y resistentes a LMs. Se encontró una sobreexpresión en los aislamientos de parásitos resistentes. Además, el tratamiento con ivermectina, a diferencia de abamectina y moxidectina, fue el único que indujo un incremento significativo de la expresión de glicoproteína-P2 en los especímenes de H. contortus resistentes recuperados de corderos tratados a los 0,5 y 1 días post-tratamiento comparado con los H. contortus recuperados de animales sin tratamiento. Como conclusión, el presente trabajo de Tesis Doctoral a través de estudios in vivo, in vitro y utilizando herramientas de la biología molecular aporta información que es de utilidad para diseñar estrategias para prologar la vida útil de las lactonas macrocíclicas siempre que sean usados de manera racional y con una base de evaluación profesional por el veterinario.Gastrointestinal parasitic diseases are the main causes of economic losses in livestock. Haemonchus contortus infection is undoubtedly the most pathogenic disease that causes the greatest losses in sheep production. The parasite control should be based on management strategies of animals and pastures together with the rational administration of anthelmintics after the appropriate parasitological diagnostic. However, in the last three decades, parasitic control has been based almost exclusively on the massive use of broad-spectrum and persistent anthelminthic drugs. The increase in anthelminthic resistance along with the new tendency of organic production and reduction of drug residues in food generated interest in the study of new control strategies. In this context, the present work of Doctoral Thesis focused on the anthelmintic resistance from an integrative pharmaco-parasitological approach. The objective of the currern work was to study the relationship that exists between the concentrations of different macrocyclic lactones in plasma, tissues / fluids of parasitic location of sheep and in the target parasite and the efficacy against resistant H. contortus. The Thesis was divided into 3 experimental sections. In the first, the in vivo characterization of factors affecting the relationship between concentrations at the site of parasitic localization, concentrations in the target parasite and anthelmintic efficacy for different macrocyclic lactones in lambs infested with resistant nematodes was evaluated under standardized conditions. Three experiments were carried out within this section, comparing the use of two administration routes (subcutaneous and intra-ruminal), the different macrocyclic lactones (ivermectin-abamectin-moxidectin) and the duplication of the dose as strategies to increase the anthelmintic efficacy. The results showed that although the plasma disposition is greater after the ivermectin administration by the subcutaneous route, higher drug concentrations were measured in the tissues and contents of the gastrointestinal tract after 2-3 days post-treatment by intraruminal route. The drug increment in the target tissues was reflected in a higher concentrations of ivermectin found within the parasite and a higher efficacy against H. contortus after the intraruminal administration. The current results corroborated that the drug entry to the parasite by the transcuticular route is relevant for clinical efficacy, even for those parasites that are hematophagous. In the second experiment, it was found that moxidectin administered at the therapeutic dose was more effective vi against nematodes resistant to ivermectin. Although moxidectin showed the lowest accumulated concentrations in adult parasites, lower number of parasites were recovered (at day 2) after moxidectin treatment and its anthelmintic efficacy was greater compared to those obtained after ivermectin and abamectin administration. In the third experiment, the influence of the dose rate on the efficacy and accumulation of drugs in the target tissues of lambs and in H. contortus was evaluated. Due to the high level of resistance, only the administration of double dose of moxidectin was effective. In Experimental Section II, the activity of macrocyclic lactones against resistant H. contortus was characterized in vitro by the development of the larval motility inhibition test using larval stages of H. contortus. This test demonstrated to be an effective test to establish differences between resistant and susceptible isolates. However, it is a difficult test to implement for the routinely diagnostic of anthelmintic resistance. An ex vivo method was also developed to characterize the entry of the drug into the adult parasites. The increased exposure to ivermectin and moxidectin enhanced the amount of drug recovered in H. contortus. In Experimental Section III, the genetic changes in H. contortus associated with the phenomenon of resistance were studied. The expression of glycoprotein-P2 in susceptible and resistant H. contortus isolates was determined. Overexpression was found in isolates of resistant parasites. In addition, treatment with ivermectin, unlike abamectin and moxidectin, was the only one that induced a significant increase in the expression of glycoprotein-P2 in resistant H. contortus recovered from treated lambs at 0.5 and 1 day post-administration. In conclusion, the present Doctoral Thesis validated in vivo and in vitro studies and molecular tools to improve the parasitic control strategies and to extend the lifespan of macrocyclic lactones. To obtain this in the field, it is necessary the rational use of these drugs in each farm with a previous professional evaluation by the veterinarians.EEA BalcarceFil: Lloberas, María Mercedes. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Balcarce; Argentina
Influence of the cattle body weight estimation for drug dosing on the pharmacokinetic and efficacy of ivermectin against Rhipicephalus (Boophilus) microplus
No full textThis study aimed to evaluate how the method of body weight estimation of a herd (average vs individual) for drug dosing may affect the pharmacokinetics and therapeutic efficacy of ivermectin 3.15% against Rhipicephalus (Boophilus) microplus. The trial was performed in two populations of R. (B.) microplus with different levels of susceptibility to ivermectin: San Martín (SM) (incipient resistance) and Colonia Benítez (CB) (susceptible). Twenty-one (SM) and forty-two (CB) 12-month-old Braford heifers, naturally infested with R. (B.) microplus, were individually weighed and divided into three groups (G). G1 and G2 were treated with a dose of ivermectin 3.15% (IVOMEC GOLD®) at a dose rate of 630 μg/kg of body weight (1 mL/50 kg). G1 received a uniform dose of ivermectin calculated according to the average of the individual body weights. G2 received a dose of ivermectin calculated according to the exact body weight of each animal. G3 were the control group. Ivermectin concentrations were measured from blood samples from day 1 to day 21 post-treatment. The efficacy of the treatment was evaluated by counting female ticks. In both populations the differences in the doses of ivermectin administered did not affect the pharmacokinetics and therapeutic efficacy of the drug. Nevertheless, it is necessary to avoid the sub-dosage of cattle to reduce the selection pressure for resistance on the tick populations.EEA RafaelaFil: Miró, María Victoria. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Centro de Investigación Veterinaria de Tandil. Laboratorio de Farmacología; Argentina.Fil: Miró, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigación Veterinaria de Tandil. Laboratorio de Farmacología; Argentina.Fil: Sarli, Macarena. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Rafaela. Instituto de Investigación de la Cadena Láctea (IDICAL); ArgentinaFil: Sarli, Macarena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigación de la Cadena Láctea (IDICAL); ArgentinaFil: Rossner, Maria Victoria. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Colonia Benitez; ArgentinaFil: Gomez, Viviana Daniela. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Colonia Benitez; ArgentinaFil: Toffaletti, Jose Rodolfo. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria El Colorado; ArgentinaFil: Lifschitz, Adrian Luis. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Centro de Investigación Veterinaria de Tandil. Laboratorio de Farmacología; Argentina.Fil: Lifschitz, Adrian Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigación Veterinaria de Tandil. Laboratorio de Farmacología; Argentina.Fil: Nava, Santiago. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Rafaela. Instituto de Investigación de la Cadena Láctea (IDICAL); ArgentinaFil: Nava, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigación de la Cadena Láctea (IDICAL); Argentin
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