Persistent efficacy of 3.5% doramectin compared to 3.15% ivermectin against gastrointestinal nematodes in experimentally-infected cattle in Brazil

The present study aimed to evaluate the persistent efficacy of a 3.5% doramectin* (700μg/kg) formulation compared to 3.15% ivermectin** (630μg/kg) treatment, administered subcutaneously at a dose of 1mL/50kg body weight in cattle experimentally infected with gastrointestinal nematodes. Seventy-two male crossbred Holstein cattle that were negative for helminth infection were divided into nine groups. Treatments of 3.5% doramectin (Groups 2, 4, 6 and 8) and 3.15% ivermectin (Groups 3, 5, 7 and 9) were administered on days 49, 42, 35 and 28 prior to challenge with infectious nematode larvae (L3). Animals in the control group (Group 1) received saline solution on day 49 before challenge. Beginning on day zero, each animal received 50mL orally of a mixed culture containing approximately 3,000 third stage larvae (L3) of Haemonchus (60%), Oesophagostomum (20%), Cooperia (15%) and Trichostrongylus (5%) for seven consecutive days, resulting in a total challenge of 21,000 larvae/animal. Due to the large number of cattle, autopsies were performed between days 28 and 35 after the last day of inoculation. The formulation containing doramectin (700 mcg/kg) achieved persistent efficacy against H. placei and C. punctata for 49 and 35days, respectively. The persistent efficacy of ivermectin (630 mcg/kg) against H. placei lasted for 49days, but this treatment was ineffective against C. punctata. Both formulations demonstrated persistent efficacy against T. axei for 49days. The persistent efficacy of doramectin (700 mcg/kg) and ivermectin (630 mcg/kg) lasted for 49 and 42days against O. radiatum, respectively. © 2012 Elsevier Ltd.

Doramectin reduces sexual behavior and penile erection in male rats

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Doramectin-Intoxikation bei drei Katzenwelpen

Dieser Fallbericht beschreibt drei Katzenwelpen mit Verdacht auf Doramectin-Intoxikation. Ein Wurf von insgesamt 7 Katzenwelpen wurde mit Doramectin behandelt, woraufhin drei Welpen neurologische Symptome entwickeltena Ein Welpe zeigte leichte Apathie und Zittern, ein weiterer zusätzlich Verhaltensänderungen und epileptiforme Anfälle, die mit Diazepam behandelt werden mussten. Beide Welpen erholten sich vollständig. Ein dritter Welpe wurde 3 Tage nach Doramectin-Gabe stuporös vorgestellt und zeigte im weiteren Verlauf Verhaltensänderungen wie Aggressivität, Hyperästhesie, Tremor und epileptiforme Anfälle. Er verstarb 36 Stunden nach Vorstellung. Bei der histopathologischen Untersuchung des Gehirns konnten ein zytotoxisches Ödem und Polioenzephalomalazie festgestellt werden. Die Doramectin-Dosis beim verstorbenen Welpen betrug 380 μg/kg.

Detection of unwanted residues of ivermectin in bovine milk by dissociation-enhanced lanthanide fluoroimmunoassay

Avermectins are frequently used to control parasitic infestations in many animal species. Previous studies have shown the long-term persistence of unwanted residues of these drugs in animal tissues and fluids. An immunoassay screening test for the detection acid quantification of ivermectin residues in bovine milk has been developed. After an extensive extraction procedure, milk samples were applied to a competitive dissociation-enhanced lanthanide fluoroimmunoassay using a monoclonal antibody against an ivermectin-transferrin conjugate, The monoclonal antibody, raised in Balb C mice, showed cross-reactivity with eprinomectin (92%), abamectin (82%) and doramectin (16%). The limit of detection of the assay (mean + 3 SD), calculated from the analysis of 17 known negative samples, was calculated as 4.6 ng/mL. Intra- and inter-assay RSDs were determined as 11.6% and 15.8%, respectively, using a negative bovine milk sample fortified with 25 ng/mL ivermectin. Six Friesian milking cows were treated with ivermectin, three with a pour-on formulation of the drug and three with an injectable solution at the manufacturer's recommended dose rate. An initial mean peak in ivermectin residue concentration was detected at day 4 (mean level = 47.5 ng/mL) and day 5 post-treatment (mean level = 26.4 ng/mL) with the injectable form and pour-on treatment, respectively. A second peak in residue concentration was observed using the DELFIA(R) procedure 28 days post-treatment in both treatment groups (23.1 ng/mL injectable and 51.9 ng/mL pour-on). These second peaks were not confirmed by HPLC and must at this Lime be considered to be false-positive results. By day 35 after treatment the mean ivermectin residue concentration of both groups fell below the limit of detection of the assay. Copyright (C) 2000 John Wiley & Sons, Ltd.

Anthelmintic drug residues in beef: UPLC-MS/MS method validation, European retail beef survey, and associated exposure and risk assessments

Anthelmintic drugs are widely used to control parasitic infections in cattle. The ProSafeBeef project addressed the need for data on the exposure of European consumers of beef to potentially harmful drug residues. A novel analytical method based on matrix solid-phase dispersive extraction and ultra-performance liquid chromatography-tandem mass spectrometry was validated for 37 anthelmintic drugs and metabolites in muscle (assay decision limits, CCa, = 0.15-10.2 µg kg -1). Seven European countries (France, Spain, Slovenia, Ireland, Italy, Belgium and Portugal) participated in a survey of retail beef purchased in local shops. Of 1061 beef samples analysed, 26 (2.45%) contained detectable residues of anthelmintic drugs (0.2-171 µg kg -1), none above its European Union maximum residue limit (MRL) or action level. Residues detected included closantel, levamisole, doramectin, eprinomectin, moxidectin, ivermectin, albendazole and rafoxanide. In a risk assessment applied to mean residue concentrations across all samples, observed residues accounted for less than 0.1% of the MRL for each compound. An exposure assessment based on the consumption of meat at the 99th percentile of consumption of adults in 14 European countries demonstrated that beef accounted for less than 0.02% of the acceptable daily intake for each compound in each country. This study is the first of its kind to apply such a risk-based approach to an extensive multi-residue survey of veterinary drug residues in food. It has demonstrated that the risk of exposure of the European consumer to anthelmintic drug residues in beef is negligible, indicating that regulation and monitoring is having the desired effect of limiting residues to non-hazardous concentrations. © 2012 Copyright Taylor and Francis Group, LLC.

Endectocide activity of a new long-action formulation containing 2.25% ivermectin+1.25% abamectin in cattle

The present work aimed to evaluate the endectocide activity of a new injectable long-action formulation, containing ivermectin (IVM) and abamectin (ABA). In each one of the four experiments performed, the following groups were formed: group I: 2.25% IVM (450 mu g/kg) + 1.25% ABA (250 mu g/kg), group II: 3.15% IVM (630 mu g/kg) and group III: control. Eighteen bovine naturally infected by gastrointestinal nematoda were selected for anthelmintic evaluation and necropsied on posttreatment day (PTD) 14 to estimate the total parasitic burden. For the Rhipicephalus (Boophilus) microplus field trial, 30 bovine were selected by means of counts of semi-engorged R. (B.) microplus and the therapeutic and residual efficacy evaluated by tick counts on PTDs 1, 3, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84 and 91. In the stall test, 15 calves were artificially infested with 5000 R. (B.) microplus (Mozzo strain) larvae three times a week and daily collections of all the engorged female ticks detached from each calf were performed until the PTD 80. Forty bovine naturally infected with Dermatobia hominis larvae were selected and the number of larvae was counted by visual and tactile inspection on PTDs 3, 7, 14, 28, 35, 49, 63, 77, 91 and 105. In this trial, a formulation containing 1% doramectin (200 mu g/kg) was also used. IVM + ABA formulation and 3.15% IVM eliminated four of the eight species of nematode identified. The anthelmintic efficacy of the avermectins association against Haemonchus placei, Cooperia spatulata and C. punctata was 89.64%, 98.84% and 97.69%, while 3.15% IVM achieved 30.98%, 84.79% and 75.56%, respectively. The two formulations evaluated showed reduced acaricide action on the PTD I and 3, reaching high efficacy percentages from PTD 14 onward. The IVM + ABA showed efficacy above 95% in the period between PTDs 21 and 49. In the stall test, it observed no difference (P > 0.05) between the two formulations regarding the R. (B.) microplus counts during the entire evaluation period. IVM + ABA reduced the number of ticks from the PTD 1 to 77 (P < 0.05) and 3.15% IVM reduced (P < 0.05) the tick number from PTD 4 up to PTD 80. The three endectocides showed no difference (P > 0.05) regarding the number of D. hominis larvae and prevented this parasite reestablishment until PTD 105. These results indicate that the IVM + ABA association showed higher anthelmintic activity and similar efficacy against arthropods to the formulation containing 3.15% IVM. (C) 2008 Elsevier B.V. All rights reserved.

Effects of macrocyclic lactones on the reproductive parameters of engorged Rhipicephalus (Boophilus) microplus females detached from experimentally infested cattle

The present study therefore assessed the deleterious effects of MLs (ivermectin, abamectin, doramectin and moxidectin) on the reproductive parameters of engorged Rhipicephalus (Boophilus) microplus females that naturally detached from experimentally infested cattle in two experiments. The following reproductive parameters of engorged female ticks were analyzed: female weight, egg mass weight, percentage of hatchability, percentage of reduction in oviposition, percentage of reduction in hatchability, reproductive efficiency and percent control/efficacy of formulations with respect to reproductive parameters. In the experiment I, statistical analysis of the data grouped into 5-days intervals revealed that pour-on application of abamectin (500. mcg/kg) had significantly (p≤. 0.05) reduced engorged female weight, egg mass weight and percent hatchability on days 6-15, 6-20 and 11-20 post-treatment (p. t.) compared to the respective data for detached and pre-selected engorged females in the control group. The abamectin, demonstrated 33.41% of reduction in oviposition, 6.77% in hatchability and abamectin efficacy was of 13.99%. In the experiment II, statistically significant reductions (p≥. 0.05) were observed in animals treated subcutaneous with ivermectin (630. mcg/kg), doramectin (700. mcg/kg) and moxidectin (1000. mcg/kg) relative to the control for days 6-40, 6-48 and 6-40 p. t., respectively. Ivermectin reduced hatchability only on days 16-20 p. t., whereas doramectin significantly reduced (p≤. 0.05) hatchability on days 6-10 and 16-35 p. t. For moxidectin, deleterious effects on hatchability were observed on days 16-35 p. t. The percent reductions in oviposition of engorged female ticks were 46.31%, 62.17% and 61.02% with ivermectin, doramectin and moxidectin treatments, respectively. The percent efficacy of the formulations on the reproductive parameters of engorged female ticks was 21.22% for ivermectin, 36.03% for doramectin and 35.45% for moxidectin. Among the MLs assessed, doramectin and moxidectin had the highest acaricidal efficacies and the most deleterious effects on the reproductive parameters of engorged R. (B.) microplus females. However, future studies will be necessary to assess the extent to which these effects, along with acaricidal activity, can be used to control the ectoparasite in cattle. © 2013 Elsevier Inc..

Farmacocinética e eficácia endectocida de uma nova formulação contendo doramectina 3,5% em bovinos

Pós-graduação em Medicina Veterinária - FCAV

Endectocide activity of a pour-on formulation containing 1.5 per cent ivermectin +0.5 per cent abamectin in cattle

The present work aimed to evaluate, through ten different studies, the therapeutic efficacy of a new pour-on formulation, containing 1.5 per cent ivermectin +0.5 per cent abamectin, against parasites of cattle. Results obtained on trials against Rhipicephalus (Boophilus) microplus showed that the pour-on combination of 1.5 per cent ivermectin +0.5 per cent abamectin obtained superior efficacy indexes against this ectoparasite, when compared with formulations containing 0.5 per cent ivermectin, 1 per cent ivermectin and the combination of 1 per cent abamectin +20 per cent levamisole. The results of efficacy of the ivermectin+abamectin and the 0.5 per cent ivermectin against Haematobia irritans were similar. Against Cochliomyia hominivorax larvae, all pour-on formulations tested (1.5 per cent ivermectin +0.5 per cent abamectin, 0.5 per cent ivermectin and 0.5 per cent abamectin), as well as 1 per cent doramectin administered subcutaneously, were considered ineffective. Cattle medicated with 1.5 per cent ivermectin +0.5 per cent abamectin, pour-on, remained free from parasitism by Dermatobia hominis larvae during 42 days (96 per cent efficacy), while values superior to 90 per cent were obtained by 0.5 per cent ivermectin (92 per cent) and 0.5 per cent abamectin (93 per cent) until the 42nd and 35th days post treatment, respectively. Against Haemonchus placei and Oesophagostomum radiatum, the pour-on of ivermectin+abamectin showed better efficacy than the 0.5 per cent ivermectin and 0.5 per cent abamectin. As to Cooperia punctata, there was no difference regarding efficacy results obtained by the avermectins combination and abamectin. The pour-on combination of 1.5 per cent ivermectin +0.5 per cent abamectin obtained high efficacy against R. (B.) microplus, D. hominis and some species of cattle gastrointestinal helminths when compared with formulations of 0.5 per cent ivermectin and 0.5 per cent abamectin administered through the same route.

Emerging contaminants in agricultural ecosystems: impact of selected pharmaceutical on water and soil ecology and pratical implications

Pharmaceuticals are useful tools to prevent and treat human and animal diseases. Following administration, a significant fraction of pharmaceuticals is excreted unaltered into faeces and urine and may enter the aquatic ecosystem and agricultural soil through irrigation with recycled water, constituting a significant source of emerging contaminants into the environment. Understanding major factors influencing their environmental fate is consequently needed to value the risk, reduce contamination, and set up bioremediation technologies. The antiviral drug Tamiflu (oseltamivir carboxylate, OC) has received recent attention due to the potential use as a first line defence against H5N1 and H1N1 influenza viruses. Research has shown that OC is not removed during conventional wastewater treatments, thus having the potential to enter surface water bodies. A series of laboratory experiments investigated the fate and the removal of OC in surface water systems in Italy and Japan and in a municipal wastewater treatment plant. A preliminary laboratory study investigated the persistence of the active antiviral drug in water samples from an irrigation canal in northern Italy (Canale Emiliano Romagnolo). After an initial rapid decrease, OC concentration slowly decreased during the remaining incubation period. Approximately 65% of the initial OC amount remained in water at the end of the 36-day incubation period. A negligible amount of OC was lost both from sterilized water and from sterilized water/sediment samples, suggesting a significant role of microbial degradation. Stimulating microbial processes by the addition of sediments resulted in reduced OC persistence. Presence of OC (1.5 μg mL-1) did not significantly affect the metabolic potential of the water microbial population, that was estimated by glyphosate and metolachlor mineralization. In contrast, OC caused an initial transient decrease in the size of the indigenous microbial population of water samples. A second laboratory study focused on basic processes governing the environmental fate of OC in surface water from two contrasting aquatic ecosystems of northern Italy, the River Po and the Venice Lagoon. Results of this study confirmed the potential of OC to persist in surface water. However, the addition of 5% of sediments resulted in rapid OC degradation. The estimated half-life of OC in water/sediment of the River Po was 15 days. After three weeks of incubation at 20 °C, more than 8% of 14C-OC evolved as 14CO2 from water/sediment samples of the River Po and Venice Lagoon. OC was moderately retained onto coarse sediments from the two sites. In water/sediment samples of the River Po and Venice Lagoon treated with 14C-OC, more than 30% of the 14C-residues remained water-extractable after three weeks of incubation. The low affinity of OC to sediments suggests that the presence of sediments would not reduce its bioavailability to microbial degradation. Another series of laboratory experiments investigated the fate and the removal of OC in two surface water ecosystems of Japan and in the municipal wastewater treatment plant of the city of Bologna, in Northern Italy. The persistence of OC in surface water ranged from non-detectable degradation to a half-life of 53 days. After 40 days, less than 3% of radiolabeled OC evolved as 14CO2. The presence of sediments (5%) led to a significant increase of OC degradation and of mineralization rates. A more intense mineralization was observed in samples of the wastewater treatment plant when applying a long incubation period (40 days). More precisely, 76% and 37% of the initial radioactivity applied as 14C-OC was recovered as 14CO2 from samples of the biological tank and effluent water, respectively. Two bacterial strains growing on OC as sole carbon source were isolated and used for its removal from synthetic medium and environmental samples, including surface water and wastewater. Inoculation of water and wastewater samples with the two OC-degrading strains showed that mineralization of OC was significantly higher in both inoculated water and wastewater, than in uninoculated controls. Denaturing gradient gel electrophoresis and quantitative PCR analysis showed that OC would not affect the microbial population of surface water and wastewater. The capacity of the ligninolytic fungus Phanerochaete chrysosporium to degrade a wide variety of environmentally persistent xenobiotics has been largely reported in literature. In a series of laboratory experiments, the efficiency of a formulation using P. chrysosporium was evaluated for the removal of selected pharmaceuticals from wastewater samples. Addition of the fungus to samples of the wastewater treatment plant of Bologna significantly increased (P < 0.05) the removal of OC and three antibiotics, erythromycin, sulfamethoxazole, and ciprofloxacin. Similar effects were also observed in effluent water. OC was the most persistent of the four pharmaceuticals. After 30 days of incubation, approximately two times more OC was removed in bioremediated samples than in controls. The highest removal efficiency of the formulation was observed with the antibiotic ciprofloxacin. The studies included environmental aspects of soil contamination with two emerging veterinary contaminants, such as doramectin and oxibendazole, wich are common parasitic treatments in cattle farms.