Comparative pharmacokinetic disposition of closantel in sheep and goats

The pharmacokinetic disposition of closantel was examined following intraruminal (i.r.) or intramuscular (i.m.) administration to adult Merino sheep and to adult and 3-month-old, suckling Angora goats. In adult goats the maximum concentration (C_max) and area under the plasma concentration with time curve ( AUC ) following 3.75, 7.5 and 15.0 mg closantel/kg given i.r. increased with dose however the time of C_max (r_max= 2.6d) in plasma was unaffected by dose rate. The elimination phase (K₁₀) of closantel was monoexponential with a half-life ( t _½) of 4.7d again unaffected by dose rate. Apart from a more rapid absorption phase and earlier T_max following 3.75 mg closantel/kg i.m., pharmacokinetic behaviour was similar to that following i.r. administration at 3.75 or 7.5 mg/kg. Although absorption rate was more rapid in kids after i.r. administration at 7.5 mg/kg, pharmacokinetic disposition of closantel was otherwise similar to that in adult goats. No closantel was detected in milk of treated does or in the plasma of their kids. I.R. closantel at 7.5 mg/kg was more slowly absorbed in goats than in sheep but C_max was similar in both species. However, K₁₀ t _½ was significantly shorter in goats (4d) than in sheep (14d). Faster elimination resulted in an almost three-fold lowering of AUC in goats and could dramatically reduce the sustained action of closantel in this species compared with sheep.     

A pharmacokinetic model to document the actual disposition of topical ivermectin in cattle

Ivermectin is a worldwide-used antiparasitic drug largely administered to cattle as a topical formulation (pour-on). The actual plasma and faecal disposition of pour-on ivermectin in cattle was documented using an original pharmacokinetic model, and taking into account the oral ingestion of the topical drug following physiological licking as a secondary route of exposure. Six pairs of monozygotic twin cattle received successively one i.v. and two pour-on administrations of ivermectin at a 3-5-month interval. For one pour-on administration, the twins were separated into an unrestrained group and a group where self- and allo-licking were prevented. Ivermectin concentrations in the plasma and faeces were determined by HPLC. Licking resulted in a high intra-and inter-individual variability of systemic exposure after topical application. By the means of pharmacokinetic modelling, we showed that 58-87% of the pour-on dose was ingested, while only 10% was absorbed percutaneously. Approximately 72% of the ingested ivermectin transited directly into the faeces, resulting in a 7-fold higher faecal excretion of the parent drug than in the non-lickers. We conclude that topical administration does not guarantee a controlled drug delivery in cattle. More importantly, the simulations revealed that non-treated cattle could get easily contaminated by allo-licking, raising the public health problem of unexpected drug residues in edible tissues.     

Effect of parasitism on the pharmacokinetic disposition of ivermectin in lambs

The aim of this study was to investigate the effect of parasitism on plasma availability and pharmacokinetic behaviour of ivermectin (IVM) in lambs. Fourteen greyface Suffolk lambs (26.8 +/- 2.2 kg body weight) were selected for this study. Seven pairs of lambs were allocated into two groups in order to obtain an approximately even distribution. Group I (non-parasitized) was pre-treated by three repeated administrations of 5 mg/kg of fenbendazole (Panacur), in order to maintain a parasite-free condition. The lambs in group II (parasitized) did not receive any anthelmintic treatment and the natural infection was sustained by an oral inoculation of infective stages of nematode parasites. After the 85-day pre-treatment period both groups of animals were treated with IVM (200 microg/kg, Ivomec) by subcutaneous injection in the shoulder area. Both groups of animals were maintained under similar conditions of feeding and management. Blood samples were collected by jugular puncture at different times between 0.5 h and 25 days post-treatment. After plasma extraction and derivatization, samples were analysed by high-performance liquid chromatography with fluorescence detection. A computerized kinetic analysis was performed and data were compared using the unpaired Student's t-test. The parent molecule was detected in plasma between 30 min and either 12 (parasitized) or 20 (no parasitized) days post-IVM treatment. The area under the curve values of the parasitized group (75.2 +/- 15.5 ng x d/ml) were significantly lower that those observed in the parasite-free group (134.3 +/- 15.7 ng x d/ml). The mean residence time (MRT) of the parasitized group (2.93 +/- 0.16 days) was significantly lower than the MRT of healthy group (3.93 +/- 0.29 days). The results of this study have shown that a change in body condition followed by a parasitic infection is associated with significant changes in plasma disposition of IVM when it is administered subcutaneously to parasitized lambs. Therefore, variations in the condition induced by parasitism should be considered when these anthelmintics are used for treating parasitized animals.     

Breed-related plasma disposition of ivermectin following subcutaneous administration in Kilis and Damascus goats

Many factors related with drug and animals affect the plasma disposition of endectocides including ivermectin (IVM). The aim of the present study was to investigate the breed differences in pharmacokinetics of IVM in goats following subcutaneous administration. Two different goat breeds (Kilis and Damascus goats) were allocated into two treatment groups with respect to breed. The injectable formulation of IVM was administered subcutaneously at a dose rate of 0.2 mg/kg bodyweight. Blood samples were collected before treatment and at various times between 1 h and 40 days after treatment and the plasma samples were analysed by high performance liquid chromatography (HPLC) using fluorescence detection. The results indicated that the plasma disposition of IVM was substantially affected by breed differences following subcutaneous administration in goats. The last detectable plasma concentration (t_last) of IVM was significantly later in Kilis goats (38.33 days) compared with Damascus goats (22.50 days). Although, there were no significant differences on C_max (10.83 ng/ml vs. 10.15 ng/ml) and t_max (2.75 days vs. 2.33 days) values; the area under the concentration–time curve-AUC (110.26 ng.d/ml vs. 73.38 ng.d/ml) the terminal half-life-t_1/2λz (5.65 days vs. 3.81 days) and the mean plasma residence time-MRT (9.31 days vs. 6.35 days) were significantly different in Kilis goats compared with Damascus goats, respectively. The breed-related difference observed on the plasma disposition of IVM between Kilis and Damascus goats could be attributable to different excretion pattern or specific anatomical and/or physiological characteristics such as body fat composition of each breed.     

Use of ivermectin to control sarcoptic mange in goats in Indonesia

Summary The results of three experiments aimed at controlling sarcoptic mange in goats in Indonesia are reported. In Experiment 1 treatment with ivermectin (0·2 mg/kg body weight) or coumaphos (0·05% dip solution) resulted in a significant reduction in mite numbers and an increase in body weight while in the untreated controls all animals had to be withdrawn from the experiment due to severity of infection. In Experiment 2 three treatment levels of ivermectin were shown to be equally effective in reducing mite numbers, while again all untreated control animals were withdrawn. The third experiment demonstrated a significantly greater reduction in mite numbers following two doses of ivermectin at a seven day interval when compared to a single dose. Again the majority of untreated control animals were withdrawn. Future control strategies and reasons for failure to eliminate the presence of mites are discussed.

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Uso De La Ivermectina Para El Control De La Sarna Sarcoptica En Cabras En Indonesia

Resumen Se describen los resultados de tres experimentos a controlar sarna sarcóptica en cabras en Indonesia. En el experimento I, el tratamiento con ivermectina (200 µg/kg de peso corporal) o con cumafos (0.05 % de una solución para baño de inmersión) dió como resultado una reducción significativa en el número de parásitos y en el incremento de peso, mientras que en el grupo de controles no tratados, todos los animales tuvieron que ser retirados del experimento debido a la severidad de la infección. En el experimento 2 tres niveles de tratamiento con ivermectina, fueron igualmente efectivos en reducir el número de ácaros; mientras que los animales no tratados tuvieron también que ser retirados. El tercer experimento dió como resultado una reducción significativa en el número de ácaros después de dos dosis de ivermectina con un intervalo de siete días, comparada con una dosis sencilla. Otra vez, la mayoría de controles no tratados tuvieron que ser retirados. Se discute en este trabajo las estrategias futuras de control y las razones de las fallas para eliminar la presencia de ácaros.

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Emploi De L'Ivermectine Pour Lutter Contre La Gale Sarcoptique Des Chevres En Indonesie

Résumé Les auteurs rapportent les résultats de 3 expériences ayant pour but la lutte contre la gale sarcoptique en Indonésie.Expérience n° 1: le traitement à l'ivermectine à la dose de 200 mg par kg de poids vif ou au coumaphos (bain en solution à 0,05 p. 100) a entraîné une réduction significative du nombre des parasites et un accroissement du poids corporel. Chez les témoins non traités au contraire, tous les animaux ont dû être retirés de l'expérience en raison de la sévérité de l'infection.Expérience n° 2: 3 niveaux de traitment par l'ivermectine ont montré une efficacité identique dans la réduction du nombre des acariens, tandis que là encore les animaux témoins non-traités ont dû être retirés.Expérience n° 3: Elle a révélé une réduction significativement plus grande dans le nombre des parasites après 2 doses d'ivermectine à sept jours d'intervalle, comparée à une dose unique. Comme dans les 2 expériences précédentes, la majorité des témoins a dû être soustraite au protocole. Les stratégies de lutte possibles et les raisons des échecs dans l'élimination des parasites font l'objet de la discussion.

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Name and address for reprints: Dr A.J. Wilson, Project Manager, RIVS, PO Box 52, Bogor, West Java, Indonesia.     

The effect of sesame and sunflower oils on the plasma disposition of ivermectin in goats

The effect of sesame oil (SSO) and sunflower oil (SFO) (the excipients) on the plasma disposition of ivermectin (IVM) following intravenous (i.v.) and subcutaneous (s.c.) administration at a dosage of 200 μg/kg was investigated in goats. Ten clinically healthy crossbred goats were used in the study. The animals were allocated by weight and sex into two groups of five animals each. Group 1 (n = 5) received the drug and excipient by the i.v. route only and group 2 received drug and excipient by the s.c. route only. The study was designed according to a two‐phase crossover design protocol. In the first phase three animals in group 1 were i.v. administered IVM (0.2 mg/kg) + SSO (1 mL) and the other two animals received IVM (0.2 mg/kg) + SFO (1 mL). In the second phase animals were crossed over and received the alternate excipient with IVM at the same dosages. In group 2 during the first phase, three animals were s.c. administered IVM (0.2 mg/kg) + SSO (1 mL) and the other two animals were received IVM (0.2 mg/kg) + SFO (1 mL). In the second phase animals were crossed over and received the alternate excipient with IVM at the same dosages. A 4‐week washout period was allowed between the two phases. In group 2 significantly increased dermal thickness was observed at the s.c. injection site of the all animals which received IVM during phase I regardless of the excipient. There was almost no change observed at the injection site of any animal during the second phase of the study following s.c. administration. In group 2 the plasma concentrations of IVM in the second phase for both excipient combinations were much higher than the plasma concentrations following first administration and appeared to be related with the dermal changes. The mean plasma disposition of IVM in combination with SSO or SFO was similar following i.v. administration. Longer terminal elimination half‐lives and resultant longer mean resident time were observed after s.c. administration of the both combinations compared with i.v. administration.     

The effect of level of feed intake on the pharmacokinetic disposition and efficacy of ivermectin in sheep

The kinetic disposition of orally administered [³H]-Ivermectin (IVM) was examined in sheep in which the feed intake was maintained at either 800 or 400 g/day. The [³H]-metabolites were almost completely associated with particulate digesta in the rumen. In the low feed intake group the digesta flow was slower than in sheep on high feed intake. This resulted in an extended residence time and greater availability of IVM and its metabolites. The anthelmintic efficacy of IVM was then examined in sheep in which feed intake was reduced from 800 g/day to 400g/36h prior to and 36 h after IVM administration. In sheep with reduced intake 97% of IVM-resistant Haemonchus contortus were removed, compared with 53% in sheep maintained on high feed intake.     

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

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

Duration of activity of topical eprinomectin against experimental infections with Teladorsagia circumcincta and Trichostrongylus colubriformis in goats

The immediate as well as the persistent anthelmintic efficacies of topically applied eprinomectin were evaluated in goats against induced infections with Teladorsagia circumcincta (2800 L3) and Trichostrongylus colubriformis (6000 L3). Twenty-three culled dairy goats were allocated to the following groups: control animals (group 1), animals treated 21 days prior to nematode infection (group 2), animals treated 7 days prior to nematode infection (group 3) and animals treated 21 days after nematode infection (group 4). Eprinomectin was applied at twice the cattle dose rate (1.0 mg/kg BW). According to the groups, necropsies were undertaken 28 days after nematode infection (groups 1-3) or 14 days after the anthelmintic treatment (group 4). Worm counts were determined for abomasum and small intestine. The curative anthelmintic efficacy of eprinomectin at 1.0 mg/kg BW on existing worm burdens was 100% against T. circumcincta and T. colubriformis. Quite similar worm burdens reductions were observed when eprinomectin was administered 7 days before infection whereas they were only 52.4 and 17.8% for T. circumcincta and T. colubriformis, respectively, for an administration of the drug 21 days prior to the nematode infection.     

Resistance of Teladorsagia circumcincta in goats to ivermectin in the Netherlands

Resistance of Teladorsagia circumcincta in goats to ivermectin In 2005, suspected ivermectin resistance of gastrointestinal nematodes was investigated in 17 goats on a farm in the Netherlands, using a faecal egg count reduction test combined with faecal larval cultures. Eight goats were treated orally with 0.2 mg/ kg ivermectin on 1 August 2005 and the other nine goats served as untreated controls. Faeces were collected from all goats on 1 August and on 12 August. Faecal egg counts were reduced by 80.6% in goats receiving ivermectin. On the basis of faecal larval cultures and the egg counts, ivermectin was found to be 100% effective against Haemonchus contortus, 15.0% effective against Teladorsagia circumcincta, and 93.3% effective against Trichostrongylus spp. The effect of levamisole and oxfendazole on gastrointestinal nematodes was also evaluated. Nine goats were treated subcutaneously with 5 mg/kg levamisole and seven goats orally with 4.5 mg/kg oxfendazole on 12 September On the basis of faecal egg counts performed on 12 and 22 September, levamisole reduced the total egg count by 95.4% and oxfendazole reduced the egg count by 85.8%. Differentiation of pooled faecal larval cultures revealed that levamisole was 99.9% effective against H. contortus, 81.9% effective against T. circumcincta, and 99.5% against Trichostrongylus spp. Oxfendazole was 75.5% effective against H. contortus, 33.2% effective against T. circumcincta, and 100% effective against Trichostrongylus spp. On 28 October the nine goats that were still present on the farm were orally treated with 0.4 mg/kg ivermectin. Faecal egg counts and differentiation of pooled larval cultures of faecal samples collected on 28 October and 9 November, respectively, revealed that total egg counts were reduced by 93.1%. Ivermectin was 49.1% effective against T. circumcincta but 100% effective against H. contortus and Trichostrongylus spp. Thus H. contortus appears to be resistant to oxfendazole and T. circumcinta appears to be resistant to oxfendazole and ivermectin. This is the first documented case of ivermectin resistance of a gastrointestinal nematode of small ruminants in the Netherlands.     

The effects of different ages and dosages on the plasma disposition and hair concentration profile of ivermectin following pour-on administration in goats

Gokbulut, C., Cirak, V.Y., Senlik, B., Aksit, D., McKellar, Q.A. The effects of different ages and dosages on the plasma disposition and hair concentration profile of ivermectin following pour‐on administration in goats. J. vet. Pharmacol. Therap. 34 , 70–75. The effects of different ages and dosages on the plasma disposition and hair degradation of ivermectin (IVM) were investigated following pour‐on administration in goats. Twenty‐eight female Saanen goats allocated into two groups of 14 animals according to their ages as young (5–6 months old) and old (12–24 months old) groups. Each age group was divided into two further of seven goats and administered pour‐on formulation of IVM topically at the in recommended dosage rate of 0.5 mg/kg bodyweight The recommended cattle dosages rate of 0.5 mg/kg or at the higher dosage of 1.0 mg/kg. Blood samples were collected at various times between 1 h and 40 days. In addition, hair samples (>0.01 g) were collected using tweezers from the application sites and far from application sites of the all animals throughout the blood sampling period. The plasma and hair samples were analyzed by high performance liquid chromatography (HPLC) using fluorescence detection following solid and liquid phase extractions, respectively. Dose‐ and age‐dependent plasma disposition of IVM were observed in goats after pour‐on administration. In addition, relatively high concentration and slow degradation of IVM in hair samples collected from the application site and far from the application site were observed in the present study. The differences between young and old goats are probably related to differences in body condition and/or lengths of haircoat. The systemic availability of IVM following pour‐on administration is relatively much lower than after oral and subcutaneous administrations but the plasma persistence was prolonged. Although, the longer persistence of IVM on hairs on the application site may prolong of efficacy against ectoparasites, the poor plasma availability could result in subtherapeutic plasma concentrations, which may confer the risk of resistance development in for internal parasites after pour‐on administration in goats.     

The distribution and some pharmacokinetic parameters of ivermectin in pigs

Ivermectin was injected subcutaneously into five pigs at the usual dose rate of 300 µg/kg and found to distribute well to all tissues and body fluids which were sampled 24 h post-injection. Ivermectin was detected in the contents and mucus at all levels of the gastrointestinal tract. The drug was excreted in bile, with high concentrations of the drug in the intestines and faeces. High concentrations of ivermectin were measured in skin, ears and ear wax, suggesting that the drug should be effective in the treatment of ectoparasitic infestations, particularly ear mites. The high lipid solubility of the drug may explain the high concentrations found in ear wax and skin. Ivermectin was also detected in the body fluids and tissues of an untreated pig penned with the treated animals. Direct contact appeared to be necessary for transfer of ivermectin from the treated to the untreated pig but coprophagia or urine drinking is a possible explanation.The pharmacokinetics of ivermectin administered subcutaneously at a dose rate of 300 µg/kg to six pigs were studied. There was marked individual variation in the pharmacokinetics of ivermectin. In one pig the area under the plasma concentration-time curve was particularly high. This may reflect individual variation in uptake and excretion of the drug. The mean elimination half-life of the drug was 35.2 h, suggesting that the drug is cleared slowly from pigs with drug detectable in plasma for 6–10 days. This persistence should allow a short period of protection before re-infection with parasites.     

The effect of breed,sex, and drug concentration on the pharmacokinetic profile of ivermectin in cattle

Ivermectin (IVM) is one of the most widely used antiparasitic drugs worldwide and has become the drug of choice for anthelmintic and tick treatment in beef cattle production. It is known that pharmacokinetic parameters are fundamental to the rational use of a drug and food safety and these parameters are influenced by different factors. The aim of this study was to evaluate the pharmacokinetic profile of IVM in Bos indicus, Bos taurus, and crossbreed cattle (B. indicus × B. taurus) kept under same field conditions and the possible impacts of sex and IVM formulation (1% and 3.15%). It was observed that IVM concentration was significantly affected by breed. The plasma concentrations of IVM, AUC, C_max, and t_1/2β were significantly higher in B. indicus compared to B. taurus. Crossbreed animals showed an intermediate profile between European and Indian cattle. No alteration in pharmacokinetics parameters was detected when comparing different gender. Concerning the pharmacokinetic data of IVM formulation, it was verified that T_max, AUC, and t_1/2β were higher in 3.15% IVM animals than those from 1% IVM formulation. The results clearly indicated that the IVM plasma concentrations in B. indicus were higher than that in B. taurus.     

Resistance to ivermectin in a field strain of Ostertagia spp. in goats

The occurrence of a field strain of Ostertagia spp. showing a resistance to ivermectin in Angora goats is reported. In a controlled anthelmintic trial using naturally-infected goats, ivermectin at a dose rate of 0.2 mg/kg demonstrated an efficacy of 87% against this strain.     

Resistance to ivermectin in a field strain of Ostertugia spp. in goats

The occurrence of a field strain of Ostertugia spp. showing a resistance to ivermectin in Angora goats is reported. In a controlled anthelmintic trial using naturallv-infected goats. ivermectin at a dose rate of 0.2 mg/ kg demonstrated an efficacy of 87% against this strain. (New Zealand Veterinary Journal 38,72–74, 1990)     

Comparative study of the efficacy of eprinomectin versus ivermectin, and field efficacy of eprinomectin only, for the treatment of chorioptic mange in alpacas

The efficacy of eprinomectin versus ivermectin (Study 1: a single-centre, randomised, treatment-controlled, blinded field trial), and the field efficacy of eprinomectin (Study 2: a single-centre, open, un-controlled field trial) for the treatment of chorioptic infestation in naturally infested alpacas were assessed in two studies. Thirty alpacas, all positive for Chorioptes sp. mite, were randomly allocated to two treatment groups in Study 1. Group A received a single topical administration of a 0.5% formulation of eprinomectin at the dose rate of 500 μg/kg. Group B received three subcutaneous administrations at 14 days interval of a 1% formulation of ivermectin at the dose rate of 400 μg/kg. Response to treatment was assessed by periodic mite count, and skin lesions scored. In Study 2, one group of 19 alpacas received four administrations at weekly interval of topical eprinomectin at the dose rate of 500 μg/kg, and response to treatment was monitored by mite counts. No localised or systemic side effects were observed in either trial. There was a statistically significant decrease in mite counts on day 7 (P < 0.001) within treatment Groups A and B of Study 1, but mite counts increased again on day 14 and remained high for the duration of the trial in both treatment groups. On day 14 of Study 2, there was a statistically significant reduction in mite counts (P < 0.008) and the mite counts remained very low throughout the remainder of the study. The eprinomectin protocol employed in Study 2, consisting of four weekly topical administrations at the dose rate of 500 μg/kg of body weight, proved highly effective at reducing the Chorioptes mite burden in alpacas.