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1. Therapeutic advantages of the combined use of closantel and moxidectin in lambs parasitized with resistant gastrointestinal nematodes

Author

Gonzalo Suárez, Daniel Castells, Fernanda Imperiale, Pietro Fagiolino, Candela Canton, Carlos Lanusse, and Luis Alvarez

Subjects
Salicylanilides, Macrocyclic lactones, Combined treatment, Co-administered, Pharmacokinetics, Efficacy, Infectious and parasitic diseases, RC109-216
Abstract

The serious widespread development of nematode resistance has motivated the use of combined anthelmintic formulations. However, the advantages/disadvantages of the combined use of anthelmintics require further scientific characterization. The goals of the current trial were a) to characterize the pharmacokinetics of closantel (CLO) and moxidectin (MXD) administered both subcutaneously (sc) and orally either separately or co-administered (CLO + MXD) to lambs; b) to compare the nematodicidal activity of both molecules given individually or co-administered to lambs infected with resistant nematodes. Seventy (70) Corriedale lambs naturally infected with multiple resistant gastrointestinal nematodes were involved in the pharmacokinetic and efficacy trials. The animals were allocated into six groups (n = 10) and treated with either CLO, MXD, or with the CLO + MXD combined formulation by both the oral and sc routes. Additionally, an untreated control group (n = 10) was included for the efficacy trial. The efficacy was estimated by the faecal egg count reduction test (FECRT). Higher systemic exposure of both CLO and MXD was observed after the sc compared to the oral administration in lambs. The combined administration of CLO + MXD did not markedly alter their disposition kinetics. At 13 days post-treatment, the administration of both molecules as a single active principle reached efficacy levels ranging between 80% (MXDoral), 84% (CLOoral), 85% (CLOsc), and 92% (MXDsc). The combined oral and sc treatments reached 99% efficacy. No adverse effects were observed after the combined treatment of CLO + MXD, and their co-administration did not show any adverse pharmacokinetic interaction. The combined effect of CLO + MXD successfully restored the maximum efficacy levels, which were not reached by the individual active ingredients.

Published
2023
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2. Pharmacological characterization of geraniol in sheep and its potential use in the control of gastrointestinal nematodes

Author

María Victoria Miró, Livio Martins Costa-Júnior, Luis Ignacio Alvarez, Carlos Lanusse, Guillermo Virkel, and Adrián Lifschitz

Subjects
Geraniol, Albendazole, Drug-interaction, Liver metabolism, Lambs, Veterinary medicine, SF600-1100
Abstract

Geraniol (GNL) was effective against gastrointestinal nematodes in vitro; nevertheless, the anthelmintic effect of phytochemicals combined with synthetic drugs has been little explored in vivo. This article characterized in vitro / in vivo the pharmacological features of GNL in sheep as well as its pharmacokinetic interaction with albendazole (ABZ). Additionally, the in vivo efficacy of GNL against Haemonchus contortus was evaluated in lambs. Liver microsomes from lambs were incubated in the absence or presence of GNL to analyze CYP1A1, CYP1A2 and FMO metabolic pathways. The effect of GNL on the hepatic sulfoxidation and sulfonation of ABZ and the ruminal sulforeduction of albendazole sulfoxide (ABZSO) was assessed. The in vivo pharmacokinetic interaction of ABZ and GNL was evaluated in lambs. The effect of GNL on the fecal egg count was evaluated in lambs infected with a resistant isolate of H. contortus. In sheep liver microsomes, the presence of 2 mM GNL reduced the CYP1A1, CYP1A2 and FMO pathways by 77.9, 90.8 and 84.5%, respectively, with respect to control (P

Published
2022
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3. Monepantel pharmaco-therapeutic evaluation in cattle: Pattern of efficacy against multidrug resistant nematodes

Author

Candela Canton, Lucila Canton, Adrian Lifschitz, María Paula Domínguez, Juan Torres, Carlos Lanusse, Luis Alvarez, Laura Ceballos, and Mariana Ballent

Subjects
Monepantel, Cattle, Resistant nematodes, Pharmaco-parasitological assessment, Infectious and parasitic diseases, RC109-216
Abstract

The goal of the current work was to perform an integrated evaluation of monepantel (MNP) pharmacokinetics (PK) and pharmacodynamics, measured as anthelmintic efficacy, after its oral administration to calves naturally infected with GI nematodes resistant to ivermectin (IVM) and ricobendazole (RBZ) on three commercial farms. On each farm, forty-five calves were randomly allocated into three groups (n = 15): MNP oral administration (2.5 mg/kg); IVM subcutaneous (SC) administration (0.2 mg/kg); and RBZ SC administration (3.75 mg/kg). Eight animals from the MNP treated group (Farm 1) were selected to perform the PK study. Drug concentrations were measured by HPLC. The efficacy was determined by the faecal egg count reduction test (FECRT). MNP and MNP-sulphone (MNPSO2) were the main analytes recovered in plasma. MNPSO2 systemic exposure was markedly higher compared to that obtained for MNP. Higher Cmax and AUC values were obtained for the active MNPSO2 metabolite (96.8 ± 29.7 ng/mL and 9220 ± 1720 ng h/mL) compared to MNP (21.5 ± 4.62 ng/mL and 1709 ± 651 ng h/mL). The MNPSO2 AUC value was 6-fold higher compared to the parent drug. Efficacies of 99% (Farm 1), 96% (Farm 2) and 98% (Farm 3) demonstrated the high activity of MNP (P

Published
2021
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4. Phytochemicals in Gastrointestinal Nematode Control: Pharmacokinetic–Pharmacodynamic Evaluation of the Ivermectin plus Carvone Combination

Author

María Victoria Miró, Livio Martins Costa-Júnior, Mercedes Lloberas, Patricia Cardozo, Carlos Lanusse, Guillermo Virkel, and Adrián Lifschitz

Subjects
carvone, ivermectin, nematode resistance, drug–drug interaction, Veterinary medicine, SF600-1100, Zoology, QL1-991
Abstract

A wide variety of plant-derived phytochemicals with anthelmintic effects have been described. Most of them have shown activity against parasites in vitro but have not been extensively explored in vivo. The aim of the current work was to study the pharmacokinetic–pharmacodynamic relationship of the combined administration of carvone (R-CNE) and ivermectin (IVM) to lambs. Three trials were conducted to evaluate the pharmacological interaction between R-CNE and IVM in lambs infected with resistant nematodes. Drug concentrations were measured in plasma, target tissues, and H. contortus by HPLC with fluorescent (IVM) and ultraviolet (R-CNE) detection. The effect of both compounds on parasites was estimated by the fecal egg count reduction. Coadministration with R-CNE significantly increased the plasma bioavailability of IVM. R-CNE showed a moderate anthelmintic effect, which was greater on the susceptible isolate of H. contortus. After the combination of R-CNE and IVM as an oral emulsion, both compounds were quantified in H. contortus recovered from infected lambs. However, R-CNE concentrations were much lower than those reported to achieve anthelmintic effects in the in vitro assays. Optimization of the pharmaceutical formulation, dose rate, and administration schedule is needed to take advantage of the intrinsic anthelmintic activity of phytochemicals.

Published
2023
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5. Corrigendum to Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial [EClinicalMedicine 37 (2021) 100,959]'

Author

Alejandro Krolewiecki, Adrián Lifschitz, Matías Moragas, Marina Travacio, Ricardo Valentini, Daniel F. Alonso, Rubén Solari, Marcelo A. Tinelli, Rubén O. Cimino, Luis Álvarez, Pedro E. Fleitas, Laura Ceballos, Marcelo Golemba, Florencia Fernández, Diego Fernández de Oliveira, German Astudillo, Inés Baeck, Javier Farina, Georgina A. Cardama, Andrea Mangano, Eduardo Spitzer, Silvia Gold, and Carlos Lanusse

Subjects
Medicine (General), R5-920
Published
2021
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6. Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial

Author

Alejandro Krolewiecki, Adrián Lifschitz, Matías Moragas, Marina Travacio, Ricardo Valentini, Daniel F. Alonso, Rubén Solari, Marcelo A. Tinelli, Rubén O. Cimino, Luis Álvarez, Pedro E. Fleitas, Laura Ceballos, Marcelo Golemba, Florencia Fernández, Diego Fernández de Oliveira, German Astudillo, Inés Baeck, Javier Farina, Georgina A. Cardama, Andrea Mangano, Eduardo Spitzer, Silvia Gold, and Carlos Lanusse

Subjects
Medicine (General), R5-920
Abstract

Background: There are limited antiviral options for the treatment of patients with COVID-19. Ivermectin (IVM), a macrocyclic lactone with a wide anti-parasitary spectrum, has shown potent activity against SARS-CoV-2 in vitro. This study aimed at assessing the antiviral effect of IVM on viral load of respiratory secretions and its relationship with drug concentrations in plasma. Methods: Proof-of-concept, pilot, randomized, controlled, outcome-assessor blinded trial to evaluate antiviral activity of high-dose IVM in 45 COVID-19 hospitalized patients randomized in a 2:1 ratio to standard of care plus oral IVM at 0·6 mg/kg/day for 5 days versus standard of care in 4 hospitals in Argentina. Eligible patients were adults with RT-PCR confirmed SARS-CoV-2 infection within 5 days of symptoms onset. The primary endpoint was the difference in viral load in respiratory secretions between baseline and day-5, by quantitative RT-PCR. Concentrations of IVM in plasma were measured. Study registered at ClinicalTrials.gov: NCT04381884. Findings: 45 participants were recruited (30 to IVM and 15 controls) between May 18 and September 9, 2020. There was no difference in viral load reduction between groups but a significant difference was found in patients with higher median plasma IVM levels (72% IQR 59–77) versus untreated controls (42% IQR 31–73) (p = 0·004). Mean ivermectin plasma concentration levels correlated with viral decay rate (r: 0·47, p = 0·02). Adverse events were similar between groups. No differences in clinical evolution at day-7 and day-30 between groups were observed. Interpretation: A concentration dependent antiviral activity of oral high-dose IVM was identified at a dosing regimen that was well tolerated. Large trials with clinical endpoints are necessary to determine the clinical utility of IVM in COVID-19. Funding: This work was supported by grant IP-COVID-19-625, Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación, Argentina and Laboratorio ELEA/Phoenix, Argentina.

Published
2021
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7. Rational Pharmacotherapy in Infectious Diseases: Issues Related to Drug Residues in Edible Animal Tissues

Author

Lucila Canton, Carlos Lanusse, and Laura Moreno

Subjects
rational use of veterinary drugs, drug residues in food, drug regulation, maximum residue limits, drug residue monitoring, drug residue effects, Veterinary medicine, SF600-1100, Zoology, QL1-991
Abstract

Drugs are used in veterinary medicine to prevent or treat animal diseases. When rationally administered to livestock following Good Veterinary Practices (GVP), they greatly contribute to improving the production of food of animal origin. Since humans can be exposed chronically to veterinary drugs through the diet, residues in food are evaluated for effects following chronic exposures. Parameters such as an acceptable daily intake (ADI), the no-observed-adverse-effect level (NOAEL), maximum residue limits (MRLs), and the withdrawal periods (WPs) are determined for each drug used in livestock. Drug residues in food exceeding the MRLs usually appear when failing the GVP application. Different factors related either to the treated animal or to the type of drug administration, and even the type of cooking can affect the level of residues in edible tissues. Residues above the MRLs can have a diverse negative impact, mainly on the consumer’s health, and favor antimicrobial resistance (AMR). Drug residue monitoring programmes are crucial to ensure that prohibited or authorized substances do not exceed MRLs. This comprehensive review article addresses different aspects of drug residues in edible tissues produced as food for human consumption and provides relevant information contributing to rational pharmacotherapy in food-producing animals.

Published
2021
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8. The Pattern of Blood–Milk Exchange for Antiparasitic Drugs in Dairy Ruminants

Author

Fernanda Imperiale and Carlos Lanusse

Subjects
dairy animals, antiparasitic drugs, rational use in parasite control, plasma–milk exchange, residues in milk dairy products, Veterinary medicine, SF600-1100, Zoology, QL1-991
Abstract

The prolonged persistence of milk residual concentration of different antiparasitic drugs in lactating dairy animals should be considered before recommending their use (label or extra-label) for parasite control in dairy animals. The partition blood-to-milk ratio for different antiparasitic compounds depends on their ability to diffuse across the mammary gland epithelium. The high lipophilicity of some of the most widely used antiparasitic drugs explains their high partition into milk and the extended persistence of high residual concentrations in milk after treatment. Most of the antiparasitic drug compounds studied were shown to be stable in various milk-related industrial processes. Thus, the levels of residues detected in raw milk can be directly applicable to estimating consumer exposure and dietary intake calculations when consuming heat-processed fluid milk. However, after milk is processed to obtain milk products such as cheese, yogurt, ricotta, and butter, the residues of lipophilic antiparasitic drugs are higher than those measured in the milk used for their elaboration. This review article contributes pharmacokinetics-based information, which is useful to understand the relevance of rational drug-based parasite control in lactating dairy ruminants to avoid undesirable consequences of residual drug concentrations in milk and derived products intended for human consumption.

Published
2021
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9. Exploring the potential of flubendazole in filariasis control: evaluation of the systemic exposure for different pharmaceutical preparations.

Author

Laura Ceballos, Charles Mackenzie, Timothy Geary, Luis Alvarez, and Carlos Lanusse

Subjects
Arctic medicine. Tropical medicine, RC955-962, Public aspects of medicine, RA1-1270
Abstract

The goal of elimination of the human filariases would benefit greatly from the use of a macrofilaricidal agent. In vivo trials in humans and many experimental animal models suggest that flubendazole (FLBZ) is a highly efficacious macrofilaricide. However, since serious injection site reactions were reported in humans after parenteral FLBZ administration, the search for alternative pharmaceutical strategies to improve the systemic availability of FLBZ and its metabolites has acquired urgency in both human and veterinary medicine. The goal of the current work was to compare the systemic exposure of FLBZ formulated as either an aqueous hydroxypropyl-β-cyclodextrin (CD) or aqueous carboxymethyl cellulose (CMC) suspension or a Tween 80-based formulation (TWEEN) in rats and jirds (Meriones unguiculatus). Healthy animals of both species were allocated into four experimental groups of 44 animals each: FLBZ-CD oral and FLBZ-CDsc, treated with the FLBZ-CD formulation by the oral or subcutaneous routes, respectively; FLBZ-TWEENsc, dosed subcutaneously with the FLBZ-TWEEN formulation; and FLBZ-CMC oral, treated orally with the FLBZ suspension. The FLBZ dose was 5 mg/kg. FLBZ and its hydrolyzed (H-FLBZ) and reduced (R-FLBZ) metabolites were recovered in plasma samples collected from rats and jirds treated with the different FLBZ formulations. In both species, FLBZ parent drug was the main analyte recovered in the bloodstream. In rats, FLBZ systemic exposure (AUC 0-LOQ) was significantly (P < 0.05) higher after the FLBZ-CD treatments, both oral (4.8 ± 0.9 µg.h/mL) and subcutaneous (7.3 ± 0.6 µg.h/mL), compared to that observed after oral administration of FLBZ-CMC suspension (0.93 ± 0.2 µg.h/mL). The same differences were observed in jirds. In both species, parenteral administration of FLBZ-TWEEN did not improve the systemic availability of FLBZ compared to FLBZ-CDoral treatment. In conclusion, formulation approaches that enhance the availability of flubendazole in the rat and jird may have therapeutic implications for a drug with poor or erratic bioavailability.

Published
2014
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11. Quantitative exposure assessment and risk characterization for fipronil residues in laying hen eggs

Author

Lucila Canton, Marcelo Signorini, Candela Canton, Paula Dominguez, Cristina Farias, Luis Alvarez, Carlos Lanusse, and Laura Moreno

Subjects
Tandem Mass Spectrometry, Eggs, Animals, Pyrazoles, Cattle, Female, Pesticides, Chickens, Food Science
Abstract

Poultry production is linked to veterinary drug use to treat diseases. Few ectoparasitic compounds are approved for poultry. Fipronil is a pesticide widely used in agriculture. It is also a drug authorized to control ectoparasites in small animals and, in some countries, in cattle. There has been evidence of fipronil extra-label use in laying hens, mainly to control the red mite Dermanyssus gallinae. Fipronil's popularity is due to its high toxicity to invertebrates. It could be metabolized to more toxic metabolites that potentially damage human health. In the present study, we carry out a quantitative exposure assessment and risk characterization for fipronil residues in laying hen eggs for local consumption in five cities of Buenos Aires province in Argentina, namely, Azul, Balcarce, Juarez, Chaves, and Tandil. Consumption surveys and egg sampling were conducted for three summer periods. Eggs were analyzed by UFLC-MS-MS. Fipronil prevalence, residue concentrations, residue stability to cooking methods, egg consumption, among the most important variables were modeled. The results indicated that 20.7% of samples contained fipronil residues. The highest residue was fipronil sulfone metabolite. Fipronil concentrations quantified ranged between 10 and 2510 ppb (median value = 150 ppb). When eggs were cooked, fipronil residues were stable. The exposure assessment and risk characterization revealed that the highest probability of consuming eggs with fipronil residues above the admissible limits was for young adults (20.8%), followed by babies (16.9%), young children (16.4%), children (13.4%), teenagers (10.3%), older adults (9.41%), and adults (8.65%). These results suggest an unacceptable risk associated with egg consumption with fipronil residues for all age groups. PRACTICAL APPLICATION: Fipronil is widely used as an extra-label way on laying hens since its use is prohibited in poultry production both in Argentina and in most countries. This molecule has been classified as Class II, a moderately hazardous pesticide because it could damage various human organs. Fipronil residues in eggs could be one of the exposure pathways for consumers. Monitoring residual levels and carrying out the health risk assessment in eggs are thus in an urge.

Published
2022
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15. Medication with fenbendazole in feed: plasma concentrations and effects on hepatic xenobiotic metabolizing enzymes in swine

Author

Paula Ichinose, María Victoria Miró, Karen Larsen, Carlos Lanusse, Adrián Lifschitz, and Guillermo Virkel

Subjects
General Veterinary, General Medicine
Abstract

Fenbendazole (FBZ), a benzymidazole (BZD) anthelmintic drug, is used for in-feed medication in pigs. BZD-containing drugs may induce cytochrome P450 isozymes (CYPs), particularly those members of the CYP1A subfamily. The current research evaluated the plasma and liver availability and metabolism of FBZ and its metabolites, oxfendazole (OFZ) and fenbendazole sulphone (FBZSO

Published
2022

18. List of contributors

Author

J.L. Aalhus, Hanne Christine Bertram, Mette Helen Bjørge Müller, J.S. Bodmer, Sarah Bonny, H.L. Bruce, Roman Buckow, Chris R. Calkins, Lucila Cantón, S. Chriki, Brian P. Dalrymple, Charlotte J.S. De Backer, Lars Ove Dragsted, Lesley L. Duffy, Bjørg Egelandsdal, M.P. Ellies-Oury, Per Ertbjerg, Mario Estévez, L. Faucitano, Narelle Fegan, D. Frank, Mohammed Gagaoua, D.E. Gerrard, Temple Grandin, Jessica A. Gray, Marion L. Greaser, Bing Guo, Wei Guo, Minh Ha, Mahdiyeh Hasani, Anna Haug, Maeve M. Henchion, Nicolas J. Herrera, Jean-François Hocquette, Liselot Hudders, J. Hughes, René Lametsch, Carlos Lanusse, Óscar López-Campos, X. Manteca, G. Martelli, S.K. Matarneh, Kim Matthews, Catherine M. McAuley, C.K. McDonnell, Rikke Miklos, Leticia Mora, Laura Moreno, Mahesh N. Nair, Azedah Namvar, E. Nannoni, Seamus O'Reilly, Niels Oksbjerg, Y. Oytam, Jan Erik Paulsen, Paula C. Pereira, Dave Pethick, Brigitte Picard, Rod Polkinghorne, Eero Puolanne, Peter Purslow, Ranjith Ramanathan, Milagro Reig, Linda M. Samuelsson, T.L. Scheffler, Nigel Scollan, H. Shi, Anita Sikes, S.L. Silva, Marianne Sødring, Philip Strydom, Arvind Subbaraj, Surendranath P. Suman, Margrethe Therkildsen, Laëtitia Théron, Fidel Toldrá, Daniel Tsegay Berhe, Arnold van Huis, Rozita Vaskoska, Filipa Vicente, Robyn D. Warner, Keith Warriner, Edward C. Webb, Elizabeth M. Webb, J.C. Wicks, J.D. Wood, C.N. Yen, and M.D. Zumbaugh

Published
2022
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20. In vitro inhibition of the hepatic S-oxygenation of the anthelmintic albendazole by the natural monoterpene thymol in sheep

Author

Guillermo Leon Virkel, Carlos Lanusse, Paula Viviani, Lívio Martins Costa, Victoria Miró, Adrian Luis Lifschitz, and Carolina Rocha

Subjects
Health, Toxicology and Mutagenesis, Monoterpene, Biology, Toxicology, 030226 pharmacology & pharmacy, Biochemistry, Albendazole, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, parasitic diseases, medicine, HEPATIC METABOLISM, Anthelmintic, Thymol, THYMOL, Pharmacology, Traditional medicine, Ciencias Veterinarias, General Medicine, Oxygenation, biology.organism_classification, In vitro, Nematode, SHEEP, chemistry, CIENCIAS AGRÍCOLAS, 030220 oncology & carcinogenesis, ALBENDAZOLE, Drug metabolism, medicine.drug
Abstract

Combinations of bioactive phytochemicals with synthetic compounds have been suggested as promissory tools for the improvement of nematode control in livestock. Bioactive phytochemicals may interfere with the activity of drug-metabolizing enzymes and delay the metabolic conversion of anthelmintics into less potent metabolites. This research assessed the effect of the monoterpene thymol (TML) on the in vitro hepatic metabolism of the anthelmintic albendazole (ABZ) in sheep. Liver microsomes from four (4) Texel lambs were incubated with ABZ (50 µM) in absence or in presence of TML (0.05?10 mM). The concentration of TML producing a 50% decrease in ABZ S-oxygenation (IC50) was 13.5 mM. The FMO-dependent S-oxygenation of ABZ was markedly inhibited by the monoterpene (54.1 ± 11.6%, p

Published
2019
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21. In vitro and in vivo effects of chlorpyrifos and cypermethrin on blood cholinesterases in sheep

Author

Karen Elizabeth Larsen, Guillermo Leon Virkel, Adrian Luis Lifschitz, and Carlos Lanusse

Subjects
Male, Insecticides, 040301 veterinary sciences, Administration, Topical, Otras Ciencias Biológicas, Biology, ACETYLCHOLINESTERASE, Cypermethrin, BUTYRYLCHOLINESTERASE, Ciencias Biológicas, 0403 veterinary science, 03 medical and health sciences, chemistry.chemical_compound, CYPERMETHRIN, Pyrethrins, Animals, 030304 developmental biology, Pharmacology, 0303 health sciences, Sheep, General Veterinary, Ciencias Veterinarias, 04 agricultural and veterinary sciences, CHLORPYRIFOS, Drug Combinations, chemistry, CIENCIAS AGRÍCOLAS, Butyrylcholinesterase, ORGANOPHOSPHATES, Acetylcholinesterase, Chlorpyrifos, Cholinesterase Inhibitors, Humanities, CIENCIAS NATURALES Y EXACTAS
Abstract

The combination of the organophosphate (OP) chlorpyrifos (CPF) and the pyrethroid cypermethrin (CPM) is commonly marketed as pour-on formulations for the control of sheep lice, ked, and blowflies. CPF irreversibly inhibits acetylcholinesterases (AChE), while pyrethroids are not AChE inhibitors. However, combinations of pyrethroids with OPs showed a highly synergistic effect on AChE inhibition. Thus, the aim of the current work was to evaluate in vitro and in vivo the inhibitory potency of both pesticides, alone and in combination with AChE and butyrylcholinesterase (BChE) activities in sheep blood. In vitro, IC50 values were similar after CPF or CPF plus CPM incubations. The pour-on coadministration of recommended doses of CPF and CPM did not cause a significant inhibition of AChE and BChE in sheep blood. Only slight percentages of inhibition of their catalytic activities were observed when both drugs were given at 4-fold higher dose rates. The lower systemic availability of topical administration of OPs in sheep may help to explain the lower degree of inhibition of blood AChE and BChE in vivo. The results emerged from this research are a further contribution to the knowledge of the risks of implementing higher dosage regimens of OPs-containing antiparasitic formulations. Fil: Larsen, Karen Elizabeth. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Laboratorio de Biología Celular y Ecotoxicología; Argentina. 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; Argentina Fil: Lifschitz, Adrian Luis. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; Argentina. 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; Argentina Fil: Lanusse, Carlos Edmundo. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; Argentina. 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; Argentina Fil: 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; Argentina. Universidad Nacional del Centro de la Provincia de Buenos Aires. Facultad de Ciencias Veterinarias. Departamento de Fisiopatología. Laboratorio de Farmacología; Argentina

Published
2019
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22. Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection

Author

Andrew Hill, Ahmed Abdulamir, Sabeena Ahmed, Asma Asghar, Olufemi Emmanuel Babalola, Rabia Basri, Carlos Chaccour, Aijaz Zeeshan Khan Chachar, Abu Tauib Mohammed Chowdhury, Ahmed Elgazzar, Leah Ellis, Jonathan Falconer, Anna Garratt, Basma Hany, Hashim A Hashim, Wasim Ul Haque, Arshad Hayat, Shuixiang He, Ramin Jamshidian, Wasif Ali Khan, Ravi Kirti, Alejandro Krolewiecki, Carlos Lanusse, Jacob Levi, Reaz Mahmud, Sermand Ahmed Mangat, Kaitlyn McCann, Anant Mohan, Mortezza Shakshi Niaee, Nurullah Okumus, Victoria Pilkington, Chinmay Saha Podder, Ambar Qavi, Houssam Raad, Mohammaed Sadegh Rezai, Surapaneni Sasank, Veerapaneni Spoorthi, Tejas Suri, Junzheng Wang, and Hannah Wentzel

Subjects
parasitic diseases
Abstract

Ivermectin is an antiparasitic drug being investigated for repurposing to SARS-CoV-2. In-vitro, ivermectin showed limited antiviral activity and a COVID-19 animal model demonstrated pathological benefits but no effect on viral RNA. This meta-analysis investigated ivermectin in 18 randomized clinical trials (2282 patients) identified through systematic searches of PUBMED, EMBASE, MedRxiv and trial registries. Ivermectin was associated with reduced inflammatory markers (C-Reactive Protein, d-dimer and ferritin) and faster viral clearance by PCR. Viral clearance was treatment dose- and duration-dependent. In six randomized trials of moderate or severe infection, there was a 75% reduction in mortality (Relative Risk=0.25 [95%CI 0.12-0.52]; p=0.0002); 14/650 (2.1%) deaths on ivermectin; 57/597 (9.5%) deaths in controls) with favorable clinical recovery and reduced hospitalization. Many studies included were not peer reviewed and meta-analyses are prone to confounding issues. Ivermectin should be validated in larger, appropriately controlled randomized trials before the results are sufficient for review by regulatory authorities.

Published
2021
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23. Iatrogenic doramectin overdosing causes toxicity in sheep: A case report

Author

Germán Cantón, Facundo Urtizbiría, María Mercedes Lloberas, Eleonora Morrell, Carlos Lanusse, and Adrián Lifschitz

Subjects
Anthelmintics, Ivermectin, Sheep, General Veterinary, Iatrogenic Disease, Animals, Sheep Diseases, Female, Parasitology
Abstract

Macrocyclic lactones are widely used endectocides in ruminants, with a high margin of safety for labeled indications. No previous report of iatrogenic doramectin overdosing has been published. We report an outbreak in a sheep flock in Northeast Patagonia, Argentina. Toxicity signs were observed in more than 10% and 59% of ewes and lambs, respectively, particularly those with low body condition, treated with doramectin 3.5% long-acting injectable formulation, presumably at the indicated dose of 700 μg/kg. Clinical signs included lethargy, mydriasis and coma. Doramectin concentration in blood samples was 826.8 (±119.3) ng/ml. Cerebrospinal fluid (CSF) and liver doramectin concentration in euthanized lambs were 3.26-4.28 ng/ml and 8506-8772 ng/g, respectively. Epidemiological and clinical information, and high doramectin concentration were sufficient to confirm the neurotoxicity. Scarce fat deposition could have altered doramectin pharmacokinetic which may have accounted for the observed neurotoxicity. Special care should be taken when animals under similar nutritional conditions are treated with macrocyclic lactones.

Published
2022
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24. ABC-transporter gene expression in ivermectin-susceptible and resistant Haemonchus contortus isolates

Author

Laura Mate, Mariana Ballent, Candela Cantón, Carlos Lanusse, Laura Ceballos, Luis Ignacio Alvarez L, and Juan Pedro Liron

Subjects
Anthelmintics, Ivermectin, Sheep, General Veterinary, Drug Resistance, Gene Expression, Sheep Diseases, General Medicine, Animals, ATP-Binding Cassette Transporters, Female, Haemonchus, Parasitology, Haemonchiasis
Abstract

Mammalian efflux transporters of the ATP-binding cassette (ABC) regulate cellular levels of endo- and xenobiotics by transporting molecules across cell membranes and are involved in diverse biological processes. Over-expression of these ABC transporters has been involved in macrocyclic lactone resistance. The main goal of this work was to compare the gene expression of the whole ABC-transporter superfamily in isolates of the sheep nematode Haemonchus contortus with different degrees of susceptibility to ivermectin (IVM). Additionally, the effects of in vivo IVM treatment were evaluated in the resistant isolates. Parasite-free Corriedale lambs were artificially infected with either IVM-susceptible or IVM-resistant H. contortus isolates. The differential expression of ABC transcripts in H. contortus female worms with differential susceptibility to IVM were assessed by RNA-seq. Additionally, the transcription levels of ABC-transporter genes in IVM-resistant adult worms recovered from treated sheep at 12 and 24 h after IVM administration were compared to those of IVM-R worms collected from untreated sheep. The comparative analysis of the ABC-transcripts revealed some minor differences in the expression levels of HCON_00042800 (pgp-3), HCON_00020200.mod (ced-7c), HCON_00085890 (abt-4), HCON_00063000 (pmp-5) and HCON_00116670 (wht-8), indicating that, at transcriptional level, these ABC-genes alone cannot explain resistance in H. contortus. HCON_00130060 (pgp-9.2) was highly differentially expressed in resistant isolates compared to susceptible ones, which agrees with previous reports suggesting that pgp-9 may be one of the most relevant candidates contributing to the multi-genic nature of the IVM resistance trait.

Published
2022
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26. Combination of bioactive phytochemicals and synthetic anthelmintics: In vivo and in vitro assessment of the albendazole-thymol association

Author

Sonia Luque, Carolina R. Silva, Adrian Luis Lifschitz, María Victoria Miró, Mercedes Lloberas, Lívio Martins Costa-Júnior, Guillermo Leon Virkel, Paula Viviani, and Carlos Lanusse

Subjects
Gastrointestinal Diseases, Phytochemicals, Cmax, Drug Resistance, Sheep Diseases, Pharmacology, Biology, Albendazole, High-performance liquid chromatography, chemistry.chemical_compound, Pharmacokinetics, In vivo, Otras Ciencias Veterinarias, medicine, Animals, Anthelmintic, METABOLIC INTERACTION, LAMBS, Thymol, THYMOL, Anthelmintics, Sheep, General Veterinary, Ciencias Veterinarias, General Medicine, Metabolism, Treatment Outcome, chemistry, CIENCIAS AGRÍCOLAS, Parasitology, Drug Therapy, Combination, ALBENDAZOLE, Helminthiasis, Animal, medicine.drug
Abstract

The search of novel strategies for anthelmintic control is a crucial need considering the widespread increase in resistant parasitic populations in livestock. Bioactive phytochemicals may contribute to improve parasite control by enhancing the effect of existing anthelmintic drugs. The aim of the current work was to evaluate the in vivo and in vitro pharmaco-chemical interaction and the in vivo efficacy of the combination of albendazole (ABZ) with thymol (TML) in lambs naturally infected with resistant gastrointestinal nematodes. Thirty (30) lambs were allocated into three experimental groups. Each group was treated orally with either ABZ (5 mg/kg), TML (150 mg/kg, twice every 24 h) or the co-administration of both compounds. Blood samples were collected between 0 and 51 h post-treatment and TML, ABZ and its metabolites were measured by HPLC. Individual faecal samples were collected at days -1 and 14 post-treatment to perform the faecal egg count reduction test. Additionally, the effect of TML on the sulphoreduction and sulphonation of ABZ sulphoxide was assessed in vitro using ruminal content and liver microsomes, respectively. The metabolism of TML in the ruminal content was very low and the monoterpene exhibited a low degree of association with the particulate phase of the ruminal content. No changes in the pharmacokinetic behavior of ABZ sulphoxide were observed in the presence of the natural product (TML). In contrast, the ABZ sulphone Cmax and AUC were lower (P 0.002 and 0.001 respectively) in the co-administered animals (0.16 ± 0.07 μg/mL and 3.63 ± 1.21 μg.h/mL) compared with those that received ABZ alone (0.45 ± 0.15 μg/mL and 9.50 ± 2.84 μg.h/mL). TML was detected in the bloodstream between 1 and 48 h post-treatment, which indicates the time of target nematodes being exposed to the bioactive monoterpene. However, the in vivo efficacy of TML was 0% and the presence of this terpene did not increase the efficacy of ABZ. The presence of TML significantly inhibited the ruminal sulphoreduction (P 0.001) and the hepatic sulphonation (P 0.001) of ABZ sulphoxide. These observations point out that in vivo pharmaco-parasitological studies are relevant to corroborate the adverse kinetic/metabolic interactions and the efficacy of bioactive natural products combined with synthetic anthelmintics. Fil: Miró, María Victoria. 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; Argentina Fil: Rocha e Silva, Carolina. Universidade Federal Do Maranhao.; Brasil Fil: Viviani, Paula. 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; Argentina Fil: Luque, Sonia. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires Sur. Estación Experimental Agropecuaria Balcarce. Agencia de Extensión Rural Balcarce; Argentina Fil: Lloberas, Maria Mercedes. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Buenos Aires Sur. Estación Experimental Agropecuaria Balcarce. Agencia de Extensión Rural Balcarce; Argentina Fil: Costa Júnior, Livio Martins. Universidade Federal Do Maranhao.; Brasil 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; Argentina Fil: 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; Argentina 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; Argentina

Published
2019

27. Assessment of the long-acting ivermectin formulation in sheep: Further insight into potential pharmacokinetic interactions

Author

Mélanie Alberich, Guillermo Leon Virkel, Paula Dominguez, Mariana Ballent, María Laura Maté, Anne Lespine, Carlos Lanusse, Adrian Luis Lifschitz, Universidad Nacional del Centro de la Provincia de Buenos Aires, Partenaires INRAE, Innovations Thérapeutiques et Résistances (InTheRes), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées

Subjects
Male, 0301 basic medicine, sheep, PHARMACOKINETICS, LONG-ACTING FORMULATION, Injections, Subcutaneous, [SDV]Life Sciences [q-bio], 030231 tropical medicine, Cmax, Pharmacology, ivermectin, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Ivermectin, Therapeutic index, Pharmacokinetics, In vivo, Otras Ciencias Veterinarias, medicine, Animals, Drug Interactions, Chromatography, High Pressure Liquid, Anthelmintics, 2. Zero hunger, ABAMECTIN, General Veterinary, urogenital system, Ciencias Veterinarias, abamectin, Drug interaction, Intestines, 030104 developmental biology, Long acting, Liver, chemistry, long-acting formulation, SHEEP, CIENCIAS AGRÍCOLAS, Delayed-Action Preparations, embryonic structures, Abamectin, IVERMECTIN, pharmacokinetics, medicine.drug
Abstract

The aim of the current study was to evaluate the in vivo pharmacokinetic of ivermectin (IVM) after the administration of a long-acting (LA) formulation to sheep and its impact on potential drug-drug interactions. The work included the evaluation of the comparative plasma profiles of IVM administered at a single therapeutic dose (200 μg/kg) and as LA formulation at 630 μg/kg. Additionally, IVM was measured in different gastrointestinal tissues at 15 days posttreatment with both IVM formulations. The impact of the long-lasting and enhanced IVM exposure on the disposition kinetics of abamectin (ABM) was also assessed. Plasma (IVM and ABM) and gastrointestinal (IVM) concentrations were analyzed by HPLC with fluorescent detection. In plasma, the calculated C max and AUC 0-t values of the IVM-LA formulation were 1.47- and 3.35-fold higher compared with IVM 1% formulation, respectively. The T 1/2ab and T max collected after administration of the LA formulation were 2- and 3.5-fold longer than those observed after administration of IVM 1% formulation, respectively. Significantly higher IVM concentrations were measured in the intestine mucosal tissues and luminal contents with the LA formulation, and in the liver, the increase was 7-fold higher than conventional formulation. There was no drug interaction between IVM and ABM after the single administration of ABM at 15 days post-administration of the IVM LA formulation. The characterization of the kinetic behavior of the LA formulation to sheep and its potential influence on drug-drug interactions is a further contribution to the field. Fil: 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; Argentina Fil: Maté, María Laura. 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; Argentina Fil: Dominguez, Maria Paula. 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; Argentina Fil: 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; Argentina Fil: Albérich, Melanie. Institut National de la Recherche Agronomique; Francia. Université de Toulouse. Innovation Therapeutic and Resistance; Francia Fil: Lespine, Anne. Institut National de la Recherche Agronomique; Francia. Université de Toulouse. Innovation Therapeutic and Resistance; Francia 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; Argentina 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; Argentina

Published
2019
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28. Pharmacokinetic-pharmacodynamic assessment of the ivermectin and abamectin nematodicidal interaction in cattle

Author

C. Canton, Mariana Ballent, Gisele Anahí Bernat, Guillermo Leon Virkel, Paula Dominguez, Adrian Luis Lifschitz, and Carlos Lanusse

Subjects
Male, 0301 basic medicine, AVERMECTINS, ANTHELMINTIC RESISTANCE, ANTHELMINTIC COMBINATIONS, 030231 tropical medicine, Population, Cattle Diseases, Context (language use), Biology, Random Allocation, Rhabditida, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Animal science, Ivermectin, Pharmacokinetics, Otras Ciencias Veterinarias, medicine, Animals, Drug Interactions, Anthelmintic, education, DRUG-DRUG INTERACTIONS, Feces, education.field_of_study, General Veterinary, urogenital system, Ciencias Veterinarias, Antinematodal Agents, General Medicine, 030108 mycology & parasitology, chemistry, CIENCIAS AGRÍCOLAS, Rhabditida Infections, Pharmacodynamics, embryonic structures, Abamectin, Cattle, Haemonchus, Parasitology, Haemonchiasis, medicine.drug
Abstract

In a context of nematodicidal resistance, anthelmintic combinations have emerged as a reliable pharmacological strategy to control gastrointestinal nematodes in grazing systems of livestock production. The current work evaluated the potential drug-drug interactions following the coadministration of two macrocyclic lactones (ML) ivermectin (IVM) and abamectin (ABM) to parasitized cattle using a pharmacokinetic/pharmacodynamic (PK/PD) approach. The kinetic behavior of both compounds administered either separately or coadministered was assessed and the therapeutic response of the combination was evaluated under different resistance scenarios. In the pharmacological trial, calves received a single subcutaneous (s.c.) injection of IVM (100 μg/Kg); a single s.c. injection of ABM (100 μg/Kg) or IVM + ABM (50 μg/Kg each) administered in different injection sites to reach a final ML dose of 100 μg/Kg (Farm 1). Plasma samples were taken from those animals up to 20 days post-treatment. IVM and ABM plasma concentrations were quantified by HPLC. A parasitological trial was carried out in three farms with different status of nematodes resistance to IVM. Experimental animals received IVM (200 μg/Kg), ABM (200 μg/Kg) or IVM + ABM (100 μg/Kg each) in Farm 2, and IVM + ABM (200 μg/Kg each) in Farms 3 and 4. The anthelmintic efficacy was determined by fecal egg count reduction test (FECRT). PK analysis showed similar trends for IVM kinetic behavior after coadministration with ABM. Conversely, the ABM elimination half-life was prolonged and the systemic exposure during the elimination phase was increased in the presence of IVM. Although IVM alone failed to control Cooperia spp., the combination IVM + ABM was the only treatment that achieved an efficacy higher than 95% against resistant Cooperia spp. in all farms. In fact, when Cooperia spp. was the main genus within the nematode population and Haemonchus spp. was susceptible or slightly resistant to ML (Farms 2 and 4), the total FECR for the combination IVM + ABM was higher than 90%. Instead, when the predominant nematode genus was a highly resistant Haemonchus spp. (Farm 3), the total FECR after the combined treatment was as low as the single treatments. Therefore, the rational use of these pharmacological tools should be mainly based on the knowledge of the epidemiology and the nematode susceptibility status in each cattle farm. Fil: 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; Argentina Fil: Cantón, Candela. 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; Argentina Fil: Dominguez, Maria Paula. 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; Argentina Fil: Bernat, Gisele. 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; Argentina 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; Argentina Fil: 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; Argentina 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; Argentina

Published
2020
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29. Fenbendazole and triclabendazole effects on CYP1A1/1A2 and FMO1/3 mRNAs in cattle liver slices: preliminary results

Author

Giantin, Mery, Laura, Maté, Tolosi, Roberta, Paula, Viviani, Adrian, Lifschitz, Carlos, Lanusse, Dacasto, Mauro, and Guillermo, Virkel

Subjects
cattle, cytochrome P450, flavin monooxygenase, cattle, liver slices, flavin monooxygenase, cytochrome P450, benzimidazole drugs, drug metabolism, induction, drug-drug interaction, benzimidazole drugs, liver slices, induction, drug metabolism, drug-drug interaction
Published
2017

30. Oral communications

Author

Alain BOUSQUET-MELOU, Jérôme Del Castillo, Francis Beaudry, Giuliano Ravasio, Aude A Ferran, Emanuela Maria MORELLO, Giorgia Della Rocca, Raffaella Barbero, Roberto Villa, Maurizio Ronci, Alassane Keita, Freddy Haesebrouck, Simon Bailey, Jin Bong Park, Claudia Zizzadoro, Alireza Hosseini, GIUSEPPE CRESCENZO, Marta Vascellari, Jonathan Elliott, Bartolomeo BIOLATTI, Carlos Lanusse, Cengiz Gokbulut, Peter Lees, Gaia Cecilia Luvoni, Pascal Sanders, Ahmadali Nikibakhsh, Petra Cagnardi, Frederic Dumoulin, María Elissondo, Marta Caruso, BAYRAM SENLIK, Gunther Schauberger, Maria Laura Mate, Vesna Jacevic, Fernando Bernardo, FLAVIA GIROLAMI, Philippe Gruet, Giovanni RE, and Georgios Batzias

Subjects
Pharmacology, General Veterinary, Biochemistry, CYP3A, Chemistry, Metabolism
Published
2009
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31. Keynote lectures

Author

Raffaella Barbero, Giovanni RE, Carlos Lanusse, and Jonathan Elliott

Subjects
Pharmacology, General Veterinary
Published
2009
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32. The Pharmacokinetics of Orally Administered Ivermectin in African Elephants (Loxodonta africana): Implications for Parasite Elimination

Author

B. Watson, L. Galvanek, A. Lifschitz, C. Stadler, M. Ballent, A. Rae Gandolf, and Carlos Lanusse

Subjects
Male, ANTHELMINTIC, Metabolic Clearance Rate, Elephants, Administration, Oral, Biology, Pharmacology, Excretion, Feces, Random Allocation, Animal science, Ivermectin, PHARMACOKINETIC, Pharmacokinetics, Oral administration, Blood plasma, medicine, Animals, ELEPHANT, Anthelmintic, Parasite Egg Count, LICE, Chromatography, High Pressure Liquid, Caloric Restriction, Cross-Over Studies, Antiparasitic Agents, Dose-Response Relationship, Drug, General Veterinary, urogenital system, Ciencias Veterinarias, General Medicine, Crossover study, CIENCIAS AGRÍCOLAS, Area Under Curve, embryonic structures, LOXODONTA AFRICANA, Female, Animal Science and Zoology, IVERMECTIN, Half-Life, medicine.drug
Abstract

Loxodonta africana are susceptible to a wide variety of parasites that are often treated with the broad spectrum antiparasitic ivermectin (IVM) based on empirical knowledge. The objectives of this study were to 1) measure plasma IVM levels following administration of 0.1 mg/kg IVM p.o., 2) compare plasma IVM levels following administration with regular versus restricted feed rations, 3) measure IVM excretion in feces, and 4) use these findings to generate dosing recommendations for this species. Using a crossover design, six African elephants were divided into two groups. Ivermectin was administered and typical grain rations were either provided or withheld for 2 hr. Blood and fecal samples were collected for 7 days following drug administration. After a 5-wk washout period, groups were switched and the procedure repeated. Plasma and fecal IVM were analyzed using high-performance liquid chromatography. There was no statistically significant difference detected in the pharmacokinetic data between the fed and fasted groups. Peak plasma concentration, area under the curve, and half-life for plasma ranged between 5.41-8.49 ng/ml, 17.1-20.3 ng × day/ml, and 3.12-4.47 day, respectively. High IVM concentrations were detected in feces. The peak concentration values in feces were between 264-311-fold higher than those obtained in plasma. The comparatively large area under the curve and short time to maximum concentration in feces indicate elimination prior to absorption of much of the drug. Plasma IVM concentrations were low when compared to other species. Based on these findings, administration of 0.2-0.4 mg/kg p.o. should be appropriate for eliminating many types of parasites in elephants, and could minimize development of parasite resistance. Fil: Gandolf, A. Rae. Pittsburgh Zoo; Estados Unidos. PPG Aquarium; Estados Unidos Fil: Lifschitz, A.. Pittsburgh Zoo; Estados Unidos. PPG Aquarium; Estados Unidos Fil: Stadler, C.. Pittsburgh Zoo; Estados Unidos. PPG Aquarium; Estados Unidos Fil: Watson, B.. PPG Aquarium; Estados Unidos. Pittsburgh Zoo; Estados Unidos Fil: Galvanek, L.. Pittsburgh Zoo; Estados Unidos. PPG Aquarium; Estados Unidos Fil: 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; Argentina Fil: Lanusse, Carlos Edmundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tandil; Argentina

Published
2009
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33. Nematodicidal activity of flubendazole and its reduced metabolite on a murine model of Trichinella spiralis infection

Author

Lucía, Urbizu, Alejandra, Confalonieri, Sergio, Sánchez Bruni, Carlos, Lanusse, and Luis, Ignacio Alvarez

Subjects
Anthelmintics, Cyclodextrins, Disease Models, Animal, Mebendazole, Mice, Mice, Inbred BALB C, Carboxymethylcellulose Sodium, Administration, Oral, Animals, Trichinellosis, Oxidation-Reduction, Trichinella spiralis
Abstract

Flubendazole (FLBZ) is a broad-spectrum benzimidazole anthelmintic compound. The parent FLBZ is metabolized to its reduced (R-FLBZ) and hydrolyzed (H-FLBZ) metabolites. There are no data on the potential nematodicidal activity of R-FLBZ, the main plasma metabolite found in sheep and mice. The goal of the current work was to assess the efficacy of FLBZ and R-FLBZ against Trichinella spiralis in a mouse model.Both compounds were administered to Balb/c mice infected with T. spiralis as either a cyclodextrin aqueous solution or as a carboxymethylcellulose suspension. Treatments were performed orally (5 mg/kg) at 1 day after infection with T. spiralis. The efficacy of the treatments was assessed at day 6 after infection.While the efficacy obtained for FLBZ and R-FLBZ administered as a solution was 94 and 98%, respectively, the efficacies obtained after the treatment with FLBZ suspensions were 38% (FLBZ) and 64% (R-FLBZ).Under the current experimental conditions, a high nematodicidal efficacy of both FLBZ and R-FLBZ administered as solution preparations was observed.

Published
2012

35. Plasma profile study of moxidectin in a cow and its suckling calf

Author

Alvinerie, M., Sutra, J. F., Carlos Lanusse, Galtier, P., Unité de recherche Pharmacologie-Toxicologie (UPT), Institut National de la Recherche Agronomique (INRA), and Revues Inra, Import

Subjects
pharmacocinétique, médicament, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV.BA] Life Sciences [q-bio]/Animal biology, [SDV]Life Sciences [q-bio], lactation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.GEN.GA] Life Sciences [q-bio]/Genetics/Animal genetics, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, vache allaitante, MOXIDECTINE, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.BC] Life Sciences [q-bio]/Cellular Biology, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, plasma, ComputingMilieux_MISCELLANEOUS, veau, [SDV.BA]Life Sciences [q-bio]/Animal biology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, lait, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Abstract

International audience

Published
1996

36. Albendazole treatment in cystic echinococcosis: pharmacokinetics and clinical efficacy of two different aqueous formulations.

Author

Laura Ceballos, Celina Elissondo, Laura Moreno, Marcela Dopchiz, Sergio Sánchez Bruni, Guillermo Denegri, Luis Alvarez, and Carlos Lanusse

Subjects
ALBENDAZOLE, ECHINOCOCCOSIS, PHARMACOKINETICS, THERAPEUTICS
Abstract

Abstract  The pharmacokinetic (PK) behaviour and clinical efficacy of albendazole (ABZ) against hydatid cysts in mice were assessed after treatment with two different ABZ pharmaceutical formulations. BalbC mice received ABZ (0.5 mg/kg) prepared either as solution or suspension (50 μg/ml) for oral administration (PK study). Blood samples were collected up to 16 h post-treatment and processed to measure ABZ/metabolites concentrations in plasma. The clinical efficacy assessment was performed in BalbC mice infected 8 months earlier with Echinococcus granulosus protoscoleces. Infected animals were allocated into three experimental treatment groups: (a) untreated control, (b) ABZ-solution treated, (c) ABZ-suspension treated. Both treated groups received ABZ (0.5 mg/kg) administered under two different therapeutic schemes: dosing every 48 h over 30 days (regimen I) or treated every 12 h during 15 days (regimen II). Experimental mice were sacrificed 12 h after treatment, and cysts were recovered, weighed and processed for transmission electron microscopy. Enhanced ABZ sulphoxide (the main ABZ metabolite) concentration profiles were measured in animals treated with the ABZ solution. Any positive clinical response was obtained after treatment every 48 h (30 days therapy). However, consistent with the observed PK results, both ABZ formulations were clinically effective in infected mice treated with a 12-h dosing interval (15 days therapy). [ABSTRACT FROM AUTHOR]

Published
2008
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38. Effect of amphiphilic surfactant agents on the gastrointestinal absorption of albendazole in cattle.

Author

Guillermo Virkel, Fernanda Imperiale, Adrián Lifschitz, Alejandra Pis, Ana Alvarez, Gracia Merino, Julio Prieto, and Carlos Lanusse

Subjects
ALBENDAZOLE, BENZIMIDAZOLES, ANTHELMINTICS, BIOAVAILABILITY, PERMEABILITY, HOLSTEIN-Friesian cattle
Abstract

Albendazole (ABZ) is a widely used broad-spectrum benzimidazole (BZD) anthelmintic. Low hydrosolubility and poor/erratic gastrointestinal (GI) absorption play against the systemic availability and resultant clinical efficacy of BZD compounds. Different strategies are currently investigated to improve their bioavailability and efficacy in different animal species and humans. Surfactant agents facilitate dissolution of lipophilic drugs and increase membrane permeability. The influence of amphiphilic surfactants on the pattern of absorption and systemic availability of ABZ and its metabolites in cattle was characterized in the current trial. Twenty (20) parasite-free Holstein calves (100–120 kg) were randomly allocated into four groups and treated intraruminally (10 mg/kg) using one of the following ABZ suspensions: control without surfactant (75/25 dimetyl sulphoxide/saline solution) (group A), 5 mM sodium taurocholate (STC) in saline solution (group B), 8.27 mM sodium lauryl sulphate (SLS) in saline solution (group C) and a commercial formulation (Valbazen®, Pfizer Inc. SA) (group D). Jugular blood samples were taken over 72 h post-treatment and plasma analysed by HPLC. Albendazole sulphoxide (ABZSO) and sulphone were the metabolites found in plasma. STC did not affect ABZ absorption while increased ABZSO peak plasma concentration (Cmax) (158% higher, P<0.001) was observed following co-administration of ABZ plus SLS, compared to the control group without surfactant. ABZSO plasma availability was significantly greater after the ABZ–SLS (164%) co-administration compared to that obtained in the control group without surfactant. A similar ABZSO plasma availability was obtained following the treatments with the ABZ-SLS and the commercially available formulation. SLS-mediated enhanced dissolution and absorption of ABZ accounted for the observed increased systemic availability of the active ABZSO metabolite in cattle. These results should be considered among strategies to improve the use of BZD anthelmintics. Copyright © 2003 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Published
2003
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