Effects of dermal application of 10.0% imidacloprid-0.08% ivermectin in ivermectin-sensitive Collies

OBJECTIVE: To evaluate the safety of dermal application of 10.0% imidacloprid-0.08% ivermectin in ivermectin-sensitive Collies at dose rates of 3 to 5 times the proposed maximum therapeutic dose. ANIMALS: 15 Collies (5 males and 10 females) that were confirmed as ivermectin-sensitive dogs. PROCEDURE: Dogs were assigned to 3 treatment groups (control, 3X, or 5X group) in a randomized block design on the basis of the maximal ivermectin-sensitivity score obtained during preliminary screening. Dogs in groups 3X and 5X were treated at 3 and 5 times the maximum label dose, respectively. Control dogs received an application of an equal volume of a nonmedicated solution. Observation and scoring on all days were conducted to specifically include neurologic signs typical of ivermectin toxicosis, including lethargy, ataxia, abnormal mydriasis, and abnormal salivation. RESULTS: None of the dogs had clinical abnormalities during the study period. CONCLUSIONS AND CLINICAL RELEVANCE: Analysis of results of this study indicates that dermal application of 10.0% imidacloprid-0.08% ivermectin is safe for use in ivermectin-sensitive Collies at dose rates of 3 or 5 times the proposed maximum therapeutic dose.     

The safety of ivermectin administered orally to pregnant mares

The effect of ivermectin on the first 3 months of equine fetal development was investigated by postnatal evaluation of ontogeny; one trial was conducted in New Jersey, USA and another was conducted simultaneously in Dammartin-en-Serve, France. A total of 58 mares were used including 32 horse-mares (USA) and 26 Welsh-type pony mares (France). An oral dose of 600 micrograms ivermectin per kilogram of body weight (therapeutic dose x 3) was given to each treated mare as a paste formulation during the first 2 weeks following refusal of breeding service and at 2-week intervals thereafter for a total of 6 doses during fetal organogenesis. Control groups were given drug-free paste vehicle at 12 weekly intervals or were not dosed. Teratogenic anatomical defects were not discernible in the progeny of either medicated or unmedicated mares. Production of weaned healthy yearlings was used as a measure of reproductive efficiency. Such yearlings were produced by 65.5% of the pregnant mares that received no ivermectin. In contrast, a higher reproductive efficiency of 75.8% occurred in pregnant mares that received six timed elevated doses of ivermectin during the first 13 weeks of fetal development. Ivermectin did not adversely affect the fertility of mares or the organogenesis of their developing foals.     

Safety study of a beef-based chewable tablet formulation of ivermectin and pyrantel pamoate in growing dogs, pups, and breeding adult dogs.

To determine the safety of a new combination of ivermectin and pyrantel (as pamoate salt) in a novel beef-based chewable tablet formulation, 3 tolerance trials were conducted and included growing dogs, pups, and breeding adult dogs. Growing dogs, given the combination orally for 5 consecutive days at recommended dosages (5 mg of pyrantel/kg of body weight, 6 micrograms of ivermectin/kg) or at twice the pyrantel dosage in combination with the recommended dosage of ivermectin, had no adverse effects. The combination also was administered to 6-week-old pups at 1, 3, and 5 times the recommended dose on 3 successive days for 3 times in 1 month. Compared with age-matched controls, treatment had no effect on clinical status, growth rate, or gross or histologic features. Breeding male and female dogs given the combination at 3 times the recommended dose for extended periods had no adverse effects, and prevalence of abnormalities in the offspring was not greater than that in nonmedicated controls.     

Biovailability of ivermectin administered orally to dogs

The bioavailability of three formulations of ivermectin was determined following oral administration to dogs. The average peak plasma level (C _max) of ivermectin administered in the standard tablet formulation at 6 and 100 µg/kg of body weight was 2.97 and 44.31 ng/g, respectively. This suggest dose-dependent pharmacokinetics.C _max and total ivermectin bioavailability, as assessed from the area under the plasma curve (AUC), were similar between two tablet formulations of ivermectin administered at 100 µg/kg. Furthermore,C _max was similar following administration of radiolabelled ivermectin at 6 µg/kg in either a beef-based chewable formulation or in the standard tablet formulation.     

Comparison of the anthelmintic efficacy of oxfendazole or ivermectin administered orally and ivermectin administered subcutaneously to sheep during the periparturient period

The suppression of nematode egg output in faeces was measured in ewes treated just before lambing with either oxfendazole or ivermectin by oral drench or with ivermectin by subcutaneous injection. Ivermectin and oxfendazole given orally were similarly effective, whereas ivermectin given by subcutaneous injection extended the period of suppressed egg output by about one week. The more persistent anthelmintic effect of ivermectin given subcutaneously was probably due to its extended half-life in the plasma of treated sheep. Plasma pepsinogen activity was less in the sheep given anthelmintic than in the untreated controls. Ivermectin caused a significantly greater reduction in pepsinogen activity than oxfendazole and was more effective when given subcutaneously than when given orally.     

Evaluation of the safety of ivermectin-praziquantel administered orally to pregnant mares

OBJECTIVE: To evaluate the safety of an orally administered ivermectin and praziquantel paste with regard to variables associated with clinical findings, parturition, lactation, maternal care, and neonate viability in pregnant mares. ANIMALS: 40 pregnant mares. PROCEDURE: Mares were randomly allocated into treatment (n = 20) and control (20) groups and administered a placebo or 3 times the therapeutic dosage of ivermectin (0.6 mg/kg) and praziquantel (4.5 mg/kg) at 14-day intervals until parturition. Physical examinations were performed on mares and their foals after parturition (on postpartum days 30, 60, and 90) to identify any drug-related effects. As an aid in assessing general health, hematologic and serum biochemical analyses were performed monthly on the mares. RESULTS: In blood constituents, minor alterations that were not biologically important were observed. Reproductive performance was not affected by the unusual treatment duration or high dosage, although the drugs were administered during a crucial period of equine embryonic development (30 to 60 days). Neither adverse effects on mares nor abortions occurred. Follow-up evaluations of the foals for a 3-month period did not detect any abnormalities. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of the ivermectin-praziquantel paste appears to be safe in pregnant mares and their foals.     

Pharmacokinetics of a novel formulation of ivermectin after administration to goats

OBJECTIVE: To evaluate the pharmacokinetics of a novel commercial formulation of ivermectin after administration to goats. ANIMALS: 6 healthy adult goats. PROCEDURE: Ivermectin (200 microg/kg) was initially administered IV to each goat, and plasma samples were obtained for 36 days. After a washout period of 3 weeks, each goat received a novel commercial formulation of ivermectin (200 microg/kg) by SC injection. Plasma samples were then obtained for 42 days. Drug concentrations were quantified by use of high-performance liquid chromatography with fluorescence detection. RESULTS: Pharmacokinetics of ivermectin after IV administration were best described by a 2-compartment open model; values for main compartmental variables included volume of distribution at a steady state (9.94 L/kg), clearance (1.54 L/kg/d), and area under the plasma concentration-time curve (AUC; 143 [ng x d]/mL). Values for the noncompartmental variables included mean residence time (7.37 days), AUC (153 [ng x d]/mL), and clearance (1.43 L/kg/d). After SC administration, noncompartmental pharmacokinetic analysis was conducted. Values of the variables calculated by use of this method included maximum plasma concentration (Cmax; 21.8 ng/mL), time to reach Cmax (3 days), and bioavailability (F; 91.8%). CONCLUSIONS AND CLINICAL RELEVANCE: The commercial formulation used in this study is a good option to consider when administering ivermectin to goats because of the high absorption, which is characterized by high values of F. In addition, the values of Cmax and time to reach Cmax are higher than those reported by other investigators who used other routes of administration.     

Evaluation of a beef-based chewable formulation of pyrantel pamoate against induced and natural infections of hookworms and ascarids in dogs.

Pyrantel pamoate, formulated in a beef-based chewable tablet, was evaluated for efficacy in dogs against induced and natural infections of Toxocara canis, Toxascaris leonina, Ancylostoma caninum and Uncinaria stenocephala. Dose titration trials were conducted in Canada, the UK and Germany in dogs treated with pyrantel (as pamoate salt) at 0, 2.5, 5 or 10 mg kg-1 body weight. These studies showed that a dose rate of 2.5 mg kg-1, the efficacy of pyrantel against adult T. canis, T. leonina, U. stenocephala and A. caninum was 76.1, 85.6, 100 and 87.9%, respectively. Efficacy at 5 mg kg-1 against the same parasites was 94.2, 92.0, 93.5 and 93.8%, respectively, and at 10 mg kg-1 efficacy was 91.2, 97.6, 98.7 and 91.3%, respectively. No adverse effects due to treatment were seen in any of these trials.     

Bioavailability of a commercial formulation of ivermectin after subcutaneous administration to sheep

OBJECTIVE: To evaluate bioavailability and other pharmacokinetic variables of a commercial formulation of ivermectin after IV administration to sheep. ANIMALS: 6 healthy adult sheep. PROCEDURES: A single dose of a commercial formulation of ivermectin (200 microg/kg) was administered IV to each sheep. After a washout period of 3 weeks, each sheep was administered ivermectin by SC injection. Plasma samples were obtained for up to 36 and up to 42 days after IV and SC administration, respectively. Ivermectin concentrations were quantified by use of high-performance liquid chromatography with fluorescence detection. RESULTS: Results obtained indicated that after IV administration, ivermectin is cleared slowly from plasma, tends to distribute and accumulate in the peripheral compartment, and is slowly eliminated from the body. After SC administration, noncompartmental analysis revealed that bioavailability of ivermectin is nearly complete (98.20%), has a slow mean absorption time of 0.96 days, and reaches a maximum plasma concentration of 19.55 ng/mL at 3.13 days. CONCLUSIONS AND CLINICAL RELEVANCE: The commercial formulation of ivermectin used in this study can be administered SC to sheep on the basis of a nearly complete bioavailability. In addition, the maximum plasma concentration and interval from SC injection until maximum plasma concentration is obtained are higher than those reported by other authors who used other routes of administration.     

Absorption of phenylbutazone from a paste formulation administered orally to the horse

The absorption pattern of phenylbutazone was studied in five horses during administration of the drug in a paste formulation on days 1, 5, 8 and 12 of a 12-day dosing schedule. Since two or more plasma concentration peaks were usually obtained following each oral dose, it was concluded that phasic absorption was a particular feature of the oil:water formulation of the product. Possible causes of this unusual absorption pattern are discussed and the therapeutic implications of both phasic absorption and the recorded values of Cmax, tmax and AUC024 for phenylbutazone and its active metabolite oxyphenbutazone are considered.     

Dermal safety study with imidacloprid/moxidectin topical solution in the ivermectin-sensitive collie

A study was conducted to determine the safety of the dermal application of 10% imidacloprid/2.5% moxidectin topical solution in ivermectin-sensitive collies. Each milliliter of this solution contains 100mg of imidacloprid and 25mg of moxidectin. A total of 21 collies were prescreened for ivermectin-sensitivity and heartworm negative status prior to selection for the study. Animals were assigned based on the maximum ivermectin-sensitivity score demonstrated during the prestudy screening. Treatment groups included a 3x and 5x test article group, and a 3x and 5x mineral oil control group. The 3x and 5x doses were administered at three and five times, respectively, the 1x dose based on the animal's body weight. On day 0, 3 of the 21 dogs were treated with dermal applications of a preliminary dose of 3x test article to screen for unexpected signs of toxicity with the remaining 18 dogs being treated with 3x mineral oil to blind for the volume of liquid applied. After no signs of toxicity were observed, these same three dogs were treated with 3x of test article and 2x mineral oil on days 28 and 56. The remaining 18 animals were equally allocated to either a 5x test article group or a 5x control group and were each treated on days 28, 56, and 84. Personnel performing observations were blinded to treatment. Observations were made for clinical signs of ivermectin sensitivity twice daily during non-dosing days. On treatment days, dogs were observed hourly for the first 4h post-treatment and at 6, 8, 12, 18 and 24h. Signs of toxicosis were not observed in any of the dogs throughout the observation period. This study demonstrated the safety of imidacloprid/moxidectin, when administered to collies testing positive for ivermectin sensitivity at dosages up to five times the maximum recommended dose.     

Persistent anthelmintic activity of topically administered ivermectin in cattle

The persistent anthelmintic effect of ivermectin as a topical treatment at 500 µg/kg was evaluated against induced infections of Ostertagia ostertagi, Trichostrongylus axei and Dictyocaulus vivparus in calves. The results showed a highly significant (P<0.001) anthelmintic activity for at least 14 days against O. oslertagi and T: axei (>99 per cent efftcacies) and for at least 28 days (98 per cent efficacy) against D. viviparus.     

Persistent anthelmintic activity of topically administered ivermectin in cattle

The persistent anthelmintic effect of ivermectin as a topical treatment at 500 microg/kg was evaluated against induced infections of Ostertagia ostertagi, Trichostrongylus axei and Dictyocaulus vivparus in calves. The results showed a highly significant (P<0.001) anthelmintic activity for at least 14 days against O. ostertagi and T.axei (>99 per cent efficacies) and for at least 28 days (98 per cent efficacy) against D. viviparus.     

Loperamide‐induced expression of immune and inflammatory genes in Collies associated with ivermectin sensitivity

This study evaluated the impact of the ABCB1‐1Δ mutation in Collies which exhibited toxicity toward ivermectin, on changes in gene expression when given the unrelated ABCB1 substrate loperamide, to identify potential biomarkers predictive of drug safety. Thirty‐two healthy intact Collies consisting of dogs with either a wild‐type, heterozygous mutant, or homozygous mutant genotype were used. Whole blood samples were collected from Collies at 0 or 5 h following administration of loperamide at a dose of 0.10 mg/kg. Whole‐genome gene expression microarray was conducted to examine for changes in gene expression. Microarray analysis identified loperamide‐induced changes in gene expression which were specifically associated with ivermectin‐sensitive phenotypes in Collies possessing the ABCB1‐1Δ mutation. Gene pathway analysis further demonstrated that the altered genes are involved in immunological disease, cell death and survival, and cellular development. Thirteen genes, including CCL8 and IL‐8, were identified. Collie dogs harboring ABCB1‐1Δ mutation which also exhibited toxicity toward ivermectin demonstrated systematic responses following loperamide treatment exhibited by altered expression of genes involved in immune and inflammatory signaling pathways. Genes such as CCL8 and IL‐8 are potential biomarkers in whole blood that may predict the safety of loperamide in dogs with ABCB1‐1? mutation associated with ivermectin sensitivity.     

Breed differences in the pharmacokinetics of ivermectin administered subcutaneously to Holstein and Belgian Blue calves

Belgian Blue (BB) cattle are very sensitive to mange caused by Psoroptes ovis and, in contrast to the case in Holstein cattle, single treatments with ivermectin do not result in complete elimination of the parasite. The objective of the present study was to determine the concentration of ivermectin in plasma, skin and hair following subcutaneous administration to Holstein and BB calves and to assess the influence of breed on drug pharmacokinetics and availability. Two groups of six healthy female Holstein and BB calves were treated with ivermectin (SC formulation) at a dose of 0.2 mg/kg. Blood, skin and hair were collected before treatment and up to 21 days after treatment. Ivermectin was analyzed in plasma and tissue by high-performance liquid chromatography (HPLC). The peak concentrations (Cmax), time-peak concentrations (Tmax), the area under the plasma concentration-time curves (AUC) and the mean residence time (MRT) were determined. The patterns of plasma and tissue ivermectin concentrations were similar in the two breeds of animals, however, the AUC and Cmax levels for plasma and skin were significantly higher in the BB calves. In hair, ivermectin was detected later than in plasma and skin, with the Tmax ranging between 4 days (Holstein group) and 6 days (BB group). The possible reasons for the significantly higher levels in plasma and skin in BB calves compared to Holstein calves are discussed.     

Pharmacokinetic studies of ivermectin: Effects of formulation

Studies are reported which describe the effects of formulation, animal species, and route of administration on the pharmacokinetics of ivermectin. Biological half-life t_1/2 increases in the order: swine (0.5 day) > dogs (1.8 day) > cattle sheep (2.8 day). Formulation modifications, based upon the solubility properties of the drug, have been directed towards the development of a nonaqueous injectable formulation for cattle and an aqueous vehicle for horses. Bioavailability following subcutaneous injection in cattle can be regulated by control of injection solvent composition: a vehicle composed of a mixed aqueous-organic solvent exhibits pharmacokinetic properties (i.e., C_p, t_1/2, AUC, and F) intermediate between those furnished by an aqueous formulation and via a purely nonaqueous solvent. The longer apparent biological half-life from this latter vehicle (t_1/2=8.3 days) confirms that a slow absorption process dominates the pharmacokinetics in the nonaqueous injectable product to produce an effective controlled-release formulation. These bioavailability results illustrate the increase in the concentration of an organic solvent and a concomitant decrease in surfactant concentration in a micellar aqueous system for prolonged drug delivery via injection.     

Pharmacokinetic studies of ivermectin: effects of formulation

Studies are reported which describe the effects of formulation, animal species, and route of administration on the pharmacokinetics of ivermectin. Biological half-life t1/2 increases in the order: swine (0.5 day) less than dogs (1.8 day) less than cattle approximately equal to sheep (2.8 day). Formulation modifications, based upon the solubility properties of the drug, have been directed towards the development of a nonaqueous injectable formulation for cattle and an aqueous vehicle for horses. Bioavailability following subcutaneous injection in cattle can be regulated by control of injection solvent composition: a vehicle composed of a mixed aqueous-organic solvent exhibits pharmacokinetic properties (i.e., Cp, t1/2, AUC, and F) intermediate between those furnished by an aqueous formulation and via a purely nonaqueous solvent. The longer apparent biological half-life from this latter vehicle (t1/2 = 8.3 days) confirms that a slow absorption process dominates the pharmacokinetics in the nonaqueous injectable product to produce an effective controlled-release formulation. These bioavailability results illustrate the increase in the concentration of an organic solvent and a concomitant decrease in surfactant concentration in a micellar aqueous system for prolonged drug delivery via injection.     

An ivermectin tablet for sheep: Efficacy against gastro-intestinal nematodes and a bioavailability comparison with a liquid ivermectin formulation

An ivermectin tablet for o ral administration to sheep was developed for use in countries where it is customary to treat sheep with anthelmintic tablets. Tablets require no special administration equipment, and offer convenience for storage and transport. The ivermectin tablet, which delivers 10 mg of ivermectin (200 μg kg⁻¹ in a 50 kg sheep), had similar bioavailability to a liquid formulation of ivermectin (IVOMEC^® Liquid for Sheep) as determined by peak plasma ivermectin concentrations and area under the concentration curve in plasma (P>0.10). In dose confirmation trials in which nematode infections were induced in helminth-naive sheep, animals treated with the ivermectin tablet had significantly fewer adult and fourth-stage larval nematodes than untreated control sheep P<0.01 with efficacies >99% against all nematode species tested. In six field trials evaluating the efficacy of the ivermectin tablet in 240 Merino sheep, the reductions in faecal nematode egg counts ranged between 98 and 100%, as determined by comparison of pre- and post-treatment counts for the ivermectin-treated group.