Plasma pharmacokinetics and faecal excretion of ivermectin, doramectin and moxidectin following oral administration in horses

The present study was carried out to investigate whether the pharmacokinetics of avermectins or a milbemycin could explain their known or predicted efficacy in the horse. The avermectins, ivermectin (IVM) and doramectin (DRM), and the milbemycin, moxidectin (MXD), were each administered orally to horses at 200 microg/kg bwt. Blood and faecal samples were collected at predetermined times over 80 days (197 days for MXD) and 30 days, respectively, and plasma pharmacokinetics and faecal excretion determined. Maximum plasma concentrations (Cmax) (IVM: 21.4 ng/ml; DRM: 21.3 ng/ml; MXD: 30.1 ng/ml) were obtained at (tmax) 7.9 h (IVM), 8 h (DRM) and 7.9 h (MXD). The area under the concentration time curve (AUC) of MXD (92.8 ng x day/ml) was significantly larger than that of IVM (46.1 ng x day/ml) but not of DRM (53.3 ng x day/ml) and mean residence time of MXD (17.5 days) was significantly longer than that of either avermectin, while that of DRM (3 days) was significantly longer than that of IVM (2:3 days). The highest (dry weight) faecal concentrations (IVM: 19.5 microg/g; DRM: 20.5 microg/g; MXD: 16.6 microg/g) were detected at 24 h for all molecules and each compound was detected (> or = 0.05 microg/g) in faeces between 8 h and 8 days following administration. The avermectins and milbemycin with longer residence times may have extended prophylactic activity in horses and may be more effective against emerging and maturing cyathostomes during therapy. This will be dependent upon the relative potency of the drugs and should be confirmed in efficacy studies.     

Faecal excretion profile of moxidectin and ivermectin after oral administration in horses

A study was undertaken to evaluate and compare faecal excretion of moxidectin and ivermectin in horses after oral administration of commercially available preparations. Ten clinically healthy adult horses, weighing 390-446 kg body weight (b.w.), were allocated to two experimental groups. Group I was treated with an oral gel formulation of moxidectin at the manufacturer's recommended therapeutic dose of 0.4 mg/kg b.w. Group II was treated with an oral paste formulation of ivermectin at the recommended dose of 0.2 mg/kg b.w. Faecal samples were collected at different times between 1 and 75 days post-treatment. After faecal drug extraction and derivatization, samples were analysed by High Performance Liquid Chromatography using fluorescence detection and computerized kinetic analysis.For both drugs the maximum concentration level was reached at 2.5 days post administration. The ivermectin treatment groups' faecal concentrations remained above the detectable level for 40 days (0.6 +/- 0.3 ng/g), whereas the moxidectin treatment group remained above the detectable level for 75 days (4.3 +/- 2.8 ng/g). Ivermectin presented a faster elimination rate than moxidectin, reaching 90% of the total drug excreted in faeces at four days post-treatment, whereas moxidectin reached similar levels at eight days post-treatment. No significant differences were observed for the values of maximum faecal concentration (C(max)) and time of C(max)(T(max)) between both groups of horses, demonstrating similar patterns of drug transference from plasma to the gastrointestinal tract. The values of the area under the faecal concentration time curve were slightly higher in the moxidectin treatment group (7104 +/- 2277 ng.day/g) but were not significantly different from those obtained in the ivermectin treatment group (5642 +/- 1122 ng.day/g). The results demonstrate that although a 100% higher dose level of moxidectin was used, attaining higher plasma concentration levels and more prolonged excretion and gut secretion than ivermectin, the concentration in faeces only represented 44.3+/- 18.0% of the total parental drug administered compared to 74.3 +/- 20.2% for ivermectin. This suggests a higher level of metabolization for moxidectin in the horse.     

Cetirizine in horses: pharmacokinetics and effect of ivermectin pretreatment

The pharmacokinetics of the histamine H(1)-antagonist cetirizine and the effects of pretreatment with the antiparasitic macrocyclic lactone ivermectin on the pharmacokinetics of cetirizine were studied in horses. After oral administration of cetirizine at 0.2 mg/kg bw, the mean terminal half-life was 3.4 h (range 2.9-3.7 h) and the maximal plasma concentration 132 ng/mL (101-196 ng/mL). The time to reach maximal plasma concentration was 0.7 h (0.5-0.8 h). Ivermectin (0.2 mg/kg bw) given orally 1.5 h before cetirizine did not affect its pharmacokinetics. However, ivermectin pretreatment 12 h before cetirizine increased the area under the plasma concentration-time curve by 60%. The maximal plasma concentration, terminal half-life and mean residence time also increased significantly following the 12 h pretreatment. Ivermectin is an inhibitor of P-glycoprotein, which is a major drug efflux transporter in cellular membranes at various sites. The elevated plasma levels of cetirizine following the pretreatment with ivermectin may mainly be due to decreased renal secretion, related to inhibition of the P-glycoprotein in the proximal tubular cells of the kidney. The pharmacokinetic properties of cetirizine have characteristics which are suitable for an antihistamine, and this substance may be a useful drug in horses.     

The effects of body composition on the pharmacokinetics of subcutaneously injected ivermectin and moxidectin in pigs

Macrocyclic lactones are characterized by their long persistence in animals because of their extensive distribution into fat. This study examined the influence of body condition on the disposition of ivermectin (IVM) and moxidectin (MXD) in blood and fat following subcutaneous (s.c.) drug administration. 'Fat' and 'thin' lines of pigs were established using two different diets. All animals were then injected with either MXD or IVM at 300 microg/kg and blood samples were taken at regular intervals until slaughter. Two IVM-treated animals from each diet group were slaughtered at either 3 days or 3 weeks posttreatment. Two MXD-treated animals from each diet group were slaughtered at 3 days, 3, 6 or 9 weeks after treatment. Samples of backfat were taken from all animals at slaughter. Fluorescence HPLC was used to determine the concentrations of MXD or IVM in the plasma and fat samples. The plasma IVM concentration peaked more rapidly in the thin IVM treated pigs compared with the fat pigs. The concentration of IVM in backfat was significantly lower in the thin animals slaughtered 3 weeks after treatment. The MXD plasma concentration peaked within the first hour in both the thin and fat groups, but from 12 h posttreatment there was a higher MXD concentration in the plasma of the fat pigs resulting in MXD being detectable in these pigs for 28 days compared with only 17 days in the thin pigs. Despite this difference in plasma persistence no differences were seen in the MXD concentration of backfat between fat and thin animals. Body condition influenced the kinetic disposition of IVM and MXD following s.c. drug administration with both drugs being less persistent in thin compared with fat animals.     

Comparative efficiency of moxidectin gel or ivermectin paste for cyathostome control in young horses

Thirty-six young horses were allocated to three similar groups. Horses in Group 1 were treated with moxidectin gel on Days 0, 90, and 180, Group 2 horses received ivermectin paste on Days 0, 60, 120, and 180, and horses in Group 3 were untreated controls. All horses were maintained on a common pasture for the first 180 days. Immediately after the final scheduled deworming, each group was moved to a separate, clean pasture where it remained until Day 360. At monthly intervals, fecal egg counts, body weights, body condition scores, and pasture larval counts were measured. The cumulative costs of both deworming regimens were calculated. Young horses treated three times at 90-day intervals with moxidectin gel had significantly lower monthly fecal egg counts than untreated controls from Days 30 through 300. Horses given ivermectin paste four times at 60-day intervals had significantly lower egg counts than controls 30 days after each treatment and 60 days after the third dose. Average daily gains of treated horses were significantly greater than controls from Days 120 through 360 (moxidectin) and from Days 210 through 360 (ivermectin). Quarterly moxidectin treatments reduced egg counts more effectively and cost less than ivermectin given bimonthly.     

Cyathostome fecal egg count trends in horses treated with moxidectin, ivermectin or fenbendazole

Commercial preparations of fenbendazole (Safe-Guard, Intervet), ivermectin (Eqvalan, Merial) or moxidectin (Quest, Fort Dodge) were administered once to horses scheduled for routine parasiticide treatment. In total, 93 horses from six cooperating farms were used in the study. Computer generated, random allocation of horses to treatment group was conducted at each farm. Fecal egg counts were determined for all horses on trial days 0, 56, 84 and 112, with corresponding calendar dates that were unique to each farm. Only strongyle egg counts from animals which were positive at day 0 were used for analysis of variance and comparisons. Counts for the three treatment groups were similar at day 0, moxidectin相似文献   

The pharmacokinetics and antiparasitic activity of ivermectin in Hutsul and Toric horses

The aim of this study was to compare the pharmacokinetics of ivermectin and its antiparasitic activity in two horse breeds. Eight Hutsul and 14 Toric horses were administered ivermectin orally at a dose of 0.2 mg/kg body weight. Blood samples were collected for 96 hr, and faecal samples were collected one day before and on days 14 and 21 after drug administration. Ivermectin concentrations in plasma samples were determined by high‐performance liquid chromatography. Ivermectin concentration was significantly higher in Toric than in Hutsul horses 90 min after ivermectin administration and was maintained at higher level for up to 96 hr. The area under the concentration versus the time curve from 0 to the last sampling point (AUC_0→t) and the maximum plasma concentration (C_max) were significantly higher in Toric than in Hutsul horses (1792.09 ± 246.22 μg × hr/L vs. 716.99 ± 255.81 μg × hr/L and 62.72 ± 17.97 ng/ml vs. 35.34 ± 13.61 ng/ml, respectively). No parasitic eggs were found in the faecal samples collected from both groups of horses on days 14 and 21 after drug administration. The obtained results indicate that although the pharmacokinetics of ivermectin may differ significantly between horse breeds, these differences do not affect the effectiveness of therapy.     

Fexofenadine in horses: pharmacokinetics, pharmacodynamics and effect of ivermectin pretreatment

The pharmacokinetics and the effects on inhibition of histamine-induced cutaneous wheal formation of the histamine H1-antagonist fexofenadine were studied in horse. The effect of ivermectin pretreatment on the pharmacokinetics of fexofenadine was also examined. After intravenous infusion of fexofenadine at 0.7 mg/kg bw the mean terminal half-life was 2.4 h (range: 2.0-2.7 h), the apparent volume of distribution 0.8 L/kg (0.5-0.9 L/kg), and the total body clearance 0.8 L/h/kg (0.6-1.2 L/h/kg). After oral administration of fexofenadine at 10 mg/kg bw bioavailability was 2.6% (1.9-2.9%). Ivermectin pretreatment (0.2 mg/kg, p.o.) 12 h before oral fexofenadine decreased the bioavailability to 1.5% (1.4-2.1%). In addition, the area under the plasma concentration-time curve decreased 27%. Ivermectin did not affect the pharmacokinetics of i.v. administered fexofenadine. Ivermectin may influence fexofenadine absorption by interfering in intestinal efflux and influx pumps, such as P-glycoprotein and the organic anion transport polypeptide family. Oral and i.v. fexofenadine significantly decreased histamine-induced wheal formation, with a maximal duration of 6 h. A pharmacokinetic/pharmacodynamic link model indicated that fexofenadine in horse has antihistaminic effects at low plasma concentrations (EC50 = 16 ng/mL). However, oral treatments of horses with fexofenadine may not be suitable due to the low bioavailability.     

Comparison of subcutaneous ivermectin and oral moxidectin for the treatment of notoedric acariasis in hamsters

Thirty hamsters diagnosed with a Notoedres infestation on the basis of their clinical signs and skin scrapings were allocated to three matched groups. The hamsters in group 1 received ivermectin at 400 microg/kg subcutaneously once a week for eight weeks, those in group 2 were treated with moxidectin at 400 microg/kg orally once a week, and those in group 3 were treated with moxidectin at the same dosage, but twice a week. The hamsters' skin lesions were scored weekly on the basis of the severity of crusting, erythema, scaling and excoriations at various sites. In all three groups the lesion scores were significantly lower after four and eight weeks, and there was no significant difference between the efficacy of the treatments. However, at the end of the treatment, skin scrapings were negative in only 60 to 70 per cent of the animals in each group.     

Comparison of the persistent activity of ivermectin, abamectin, doramectin and moxidectin in cattle in Zambia

The persistent efficacy of four commercially available macrocyclic lactones (ML) in maintaining reduced faecal egg counts in cattle grazing naturally infested pastures was evaluated in 44 zebu animals aged 1–2 years in Zambia. The study started in February (rainy season) when the strongyle egg output was increasing. Four days before the start of the trial, all animals were treated with a double dose of oxfendazole. They were then divided into five groups which were again treated on day 0. Groups A, D, I and M received 0.2 mg kg⁻¹ of abamectin, doramectin, ivermectin and moxidectin, respectively. Animals of group C received albendazole (7.5 mg kg⁻¹). Faecal samples were collected twice a week for egg counts and larval differentiation. Faecal egg counts in the C group increased from day 21 onwards and plateaued from day 42 between 180 and 380 eggs per gram. The main genera found in cultures were Cooperia (90%) and Haemonchus (7%). Faecal egg excretion in groups M, A, D and I started on day 35, 42, 42 and 45, respectively. subsequently and until day 84, average counts in these four groups were always significantly lower than in group C. Compared with albendazole, all four ML gave over 95% reduction in cumulative faecal egg counts for 42 days after treatment. The percentage efficacy was still over 84% by day 84 when an average cumulative egg count of 11 320 eggs per gram faeces was calculated in group C. In addition, there was no significant difference in efficacy between the four ML groups at any of the sampling dates. During the trial no significant difference in weight gain between any of the groups was observed.     

Decreased ivermectin and moxidectin sensitivity in Haemonchus contortus selected with moxidectin over 14 generations.

Ivermectin resistance in the nematode Haemonchus contortus has been reported in many parts of the world and many ivermectin resistant isolates have been found to have reduced sensitivity to moxidectin. However, it is unclear whether parasites that are selected with moxidectin would demonstrate reduced sensitivity to ivermectin. In this study, the effects of moxidectin and ivermectin on an unselected strain and a strain of H. contortus derived from the unselected strain but selected over 14 generations with moxidectin, were compared in jirds. The recovery of adult worms and fourth stage (L4) larvae following treatment were compared between strains and anthelmintics. Moxidectin-selected H. contortus showed reduced sensitivity to ivermectin as well as to moxidectin. Doses of 0.1 mg/kg of moxidectin and 0.4 mg/kg of ivermectin were necessary to obtain an efficacy of 95% or above against the moxidectin-selected strain of H. contortus compared with 0.025 mg/kg for moxidectin and 0.1 mg/kg for ivermectin required for a similar efficacy in the unselected strain.     

Efficacy of ivermectin and moxidectin against Otostrongylus circumlitus and Parafilaroides gymnurus in harbour seals (Phoca vitulina)

Verminous bronchopneumonia caused by infection with Otostrongylus circumlitus and Parafilaroides gymnurus is an important cause of death during the rehabilitation of harbour seals (Phoca vitulina). During the winter of 2000/01, 35 juvenile harbour seals with severe clinical signs of verminous bronchopneumonia were treated with either 0.2 mg/kg ivermectin orally or 0.2 mg/kg moxidectin subcutaneously, and monitored for 30 days. The efficacy of the anthelmintics was determined by the pattern of larval excretion (Baermannisation) and the progress of the clinical signs. Both anthelmintics had reduced larval excretion by at least 99 per cent after 10 days, but the seals' rapid breathing rate and and dyspnoea returned to normal more quickly in the animals treated with moxidectin. The pharmacokinetics of the anthelmintics were determined by solid-phase extraction, and high-performance liquid chromatography with fluorescence detection. Moxidectin had a mean (sd) residence time of 9.04 (2.12) days compared with 4.83 (1.14) days for ivermectin.     

Comparative long-term efficacy of ivermectin and moxidectin over winter in Canadian horses treated at removal from pastures for winter housing

The impact of a late fall treatment on the spring rise of fecal egg counts was evaluated in a controlled study with Canadian horses treated with 2 different dewormers immediately after removal from pasture for winter housing. The horses were stabled until the end of the trial period. Seventeen weanlings, 20 yearlings, and 15 2-year-old horses located in Ontario, which were presumed to be naturally infected with cyathostomins after pasture grazing, were randomly allocated to either a group treated with 0.4 mg/kg of moxidectin and 2.5 mg/kg of praziquantel or a group treated with 0.2 mg/kg of ivermectin and 1.5 mg/kg of praziquantel. Three weeks after treatment, all strongyle fecal egg counts were reduced to zero for both treatment groups. However, at 5 months post-treatment, mean geometric fecal egg counts were statistically higher for the yearlings and 2-year-old horses treated with ivermectin than for the yearlings and 2-year-old horses treated with moxidectin (P < 0.0001).     

A review of the use of moxidectin in horses

Moxidectin has broad‐spectrum anti‐nematodal and anti‐arthropodal activities in the horse but is not effective against tapeworms or flukes. Moxidectin and ivermectin have the same efficacy against internal, adult parasites of horses. Moxidectin, however, is highly effective in eliminating encysted and hypobiotic larval stages of cyathostomins, whereas ivermectin is not. Treatment of horses with moxidectin results in an egg‐reappearance period (ERP) of 15–24 weeks. Because of its long ERP, moxidectin is labelled to be used at 12 week intervals. Moxidectin may provide protection against infection by ingested cyathostomin larvae for 2–3 weeks after it is administered. The larvicidal activity of moxidectin has often been compared to that of fenbendazole administered at either 7.5 or 10 mg/kg bwt for 5 consecutive days. The efficacy of fenbendazole, when administered daily for 5 consecutive days at 7.5 or 10 mg/kg bwt, against all stages of cyathostomins is often less than that of moxidectin because resistance of cyathostomins to benzimidazoles is prevalent worldwide, and the 5 day course of fenbendazole does not overcome this resistance. There are now reports of resistance of ascarids to moxidectin. Overt resistance of cyathostomins and a shortened egg re‐emergence period after treatment with moxidectin have been reported. Rapid removal of manure by natural fauna can significantly reduce larval nematode concentrations and thereby reduce intervals of anthelmintic treatment. Of the macrocyclic lactones, moxidectin has the least deleterious effect on faecal fauna.     

Efficacy and pharmacokinetics of febantel and ivermectin in red deer (Cervus elaphus)

A trial was conducted to determine the efficacy and pharmacokinetics of fehantel and ivermectin in six month-old red deer calves (C. eluphus). Five calves received febantel by mouth at 7.5 mg/kg, five received a subcutaneous injection of ivermectin at 200 microg/kg and five were controls. All calves were killed seven days later and total lung and gastrointestinal worm counts carried out. Febantel was 85 and 99.8% efficient in removing immature and mature Dictyocaulus viviparus, respectively, and ivermectin was 100% efficient in both cases. There was no gastro-intestinal nematodes in any of the treated calves, compared to an average of 619 in the control calves. The metabolism of febantel resulted in plasma levels of fenbendazole, oxfendazole and sulphone for which the common curves fitted by compartmental model peaked at values (standard errors)-of 0.46 (0.03), 0.41 (0.02) and 1.73 (0.07) mg/l after approximately five, nine, and thirteen hours and were undetectable at 30,72 and 120 hours respectively. There was considerable variation among animals in response to ivermectin. The fitted common curve had a peak plasma level of 15.8 (0.08) microg/l at 20 hours after injection, which had dropped to 7.9 (1.1) microg/l seven days after injection. It was estimated that after 15 days plasma levels of ivermectin would not be detectable. It is concluded that the injectable form of ivermectin tested is a highly efficient anthelmintic in deer, and that plasma levels persist for over a week after subcutaneous injection. Fehantel is very efficient against mature D. viviparus in deer, but its reduced efficiency against immature D. viviparus may relate to the deer;s ability to metabolise and excrete benzimidazoles more quickly than sheep and cattle.     

A comparative kinetic study of ivermectin and moxidectin in lactating camels (Camelus dromedarius).

The plasma and milk kinetics of ivermectin (IVM) and moxidectin (MXD) was evaluated in lactating camels treated subcutaneously (0.2 mg kg(-1)) with commercially available formulations for cattle. Blood and milk samples were taken concurrently at predetermined times from 12 h up to 60 days post-administration. No differences were observed between plasma and milk kinetics of IVM, while substantial differences were noted between plasma and milk profiles of MXD in that both the maximal concentration (Cmax) and the area under concentrations curves (AUC) were three to four-fold higher for milk than for plasma. The time (Tmax) to reach Cmax was significantly faster for MXD (1.0 day) than that for IVM (12.33 days). The Cmax and the AUC were significantly higher for MXD (Cmax = 8.33 ng ml(-1); AUC = 70.63 ng day ml(-1)) than for IVM (Cmax = 1.79 ng ml(-1); AUC = 30.12 ng day ml(-1)) respectively. Drug appearance in milk was also more rapid for MXD (Tmax = 3.66 days) compared to IVM (Tmax = 17.33 days). The extent of drug exchange from blood to milk, expressed by the AUCmilk/AUCplasma ratio, was more than three-fold greater for MXD (4.10) compared to that of IVM (1.26), which is consistent with the more lipophilic characteristic of MXD. However, the mean residence time (MRT) was similar in both plasma and milk for each drug.