Bruce N. Kunkle

Comparison of efficacy and safety of paste formulations of firocoxib and phenylbutazone in horses with naturally occurring osteoarthritis

OBJECTIVE To compare efficacy and safety of paste formulations of firocoxib and phenylbutazone in horses with naturally occurring osteoarthritis. DESIGN Randomized controlled clinical trial. ANIMALS 253 client-owned horses with naturally occurring osteoarthritis. PROCEDURES Horses were treated with firocoxib (0.1 mg/kg [0.045 mg/lb], PO, q 24 h) or phenylbutazone (4.4 mg/kg [2 mg/lb], PO, q 24 h) for 14 days. Physical examinations and lameness evaluations were performed prior to treatment and after 7 and 14 days. Clinical improvement was defined as a reduction of at least 1 lameness grade or a combined reduction of at least 3 points in scores for pain during manipulation or palpation, joint swelling, joint circumference, and range of motion. RESULTS Proportion of horses clinically improved on day 14 for the firocoxib group (104/123 [84.6%]) was not significantly different from the proportion for the phenylbutazone group (103/119 [86.6%]). Proportion of horses that were improved on day 14 was significantly greater for horses treated with firocoxib than for horses treated with phenylbutazone with regard to score for pain on manipulation or palpation (P = 0.028), joint circumference score (P = 0.026), and range of motion score (P = 0.012), but not for overall lameness score or joint swelling score. No direct treatment-related adverse effects were detected during the study. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that overall clinical efficacy of a paste formulation of firocoxib in horses with naturally occurring osteoarthritis was comparable to efficacy of a paste formulation of phenylbutazone.

Persistent efficacy of topical eprinomectin against nematode parasites in cattle

Abstract Six studies were conducted to evaluate the persistent efficacy of eprinomectin pour-on against experimental challenges with infective nematode larvae in calves. In each study, calves were randomly assigned to one untreated group and up to four test groups, which were treated with eprinomectin at 500 μg/kg body weight at weekly intervals before single bolus challenge. The calves were necropsied approximately 4 weeks after challenge infection for nematode recovery. Eprinomectin pour-on provided ≥90% efficacy against challenge with Haemonchus placei, Trichostrongylus axei and T. colubriformis at 21 days after treatment and against Cooperia oncophora, C. punctata, C. surnabada, Dictyocaulus viviparus, Nematodirus helvetianus, Oesophagostomum radiatum and Ostertagia ostertagi at 28 days after treatment.

Assessment of the efficacy of orally administered afoxolaner against Rhipicephalus sanguineus sensu lato.

Two studies were conducted to confirm that a single oral dose of the novel insecticide/acaricide afoxolaner is efficacious against existing infestations of Rhipicephalus sanguineus sensu lato in dogs and can control re-infestation for up to 35 days. Each study utilized 16 purpose bred adult dogs using a controlled randomized block design. One or two days prior to treatment, all dogs were infested with 50 unfed adult ticks. On Day 0 one group was treated with an oral chewable formulation of afoxolaner at a dose as close as possible to the minimum dose of 2.5mg/kg. Weekly re-infestations with 50 adult unfed ticks were repeated for five weeks. Forty-eight hours after treatment and after each re-infestation, the number of remaining live ticks on each dog was counted. Treatment with afoxolaner resulted in efficacies of 98.8-100% within 48 h on existing tick infestations, while the efficacy against new tick infestations was >95.7% over five weeks.

Nematode burdens of pastured cattle treated once at turnout with eprinomectin extended-release injection.

The efficacy of eprinomectin in an extended-release injection (ERI) formulation was evaluated against infections with third-stage larvae or eggs of gastrointestinal and pulmonary nematodes in cattle under 120-day natural challenge conditions in a series of five studies conducted in the USA (three studies) and in Europe (two studies). For each study, 30 nematode-free (four studies) or 30 cattle harboring naturally acquired nematode infections (one study) were included. The cattle were of various breeds or crosses, weighed 107.5-273 kg prior to treatment and aged approximately 4-11 months. For each study, animals were blocked based on pre-treatment bodyweight and then randomly allocated to treatment: ERI vehicle (control) at 1 mL/50 kg bodyweight or Eprinomectin 5% (w/v) ERI at 1 mL/50 kg bodyweight (1.0 mg eprinomectin/kg) for a total of 15 and 15 animals in each group. Treatments were administered once on Day 0 by subcutaneous injection in front of the shoulder. In each study, all animals grazed one naturally contaminated pasture for 120 days. At regular intervals during the studies, fecal samples from all cattle were examined for nematode egg and larval counts. In four studies pairs of tracer cattle were used to monitor pasture infectivity at 28-day intervals before and/or during the grazing period. All calves were weighed before turnout onto pasture and at regular intervals until housing on Day 120. For parasite recovery, all study animals were humanely euthanized 27-30 days after removal from pasture. Cattle treated with Eprinomectin ERI had significantly (p<0.05) fewer strongylid eggs (≤1 egg per gram; egg count reduction≥94%) than the control cattle and zero lungworm larvae at each post-treatment time point. At euthanasia, cattle treated with Eprinomectin ERI had significantly (p<0.05) fewer of the following nematodes than the ERI vehicle-treated (control) cattle with overall reduction of nematode counts by >92%: Dictyocaulus viviparus (adults and fourth-stage larvae (L4), Bunostomum phlebotomum, Cooperia curticei, Cooperia oncophora, Cooperia punctata, Cooperia surnabada, Cooperia spp. inhibited L4, Haemonchus contortus, Haemonchus placei, Haemonchus spp. inhibited L4, Nematodirus helvetianus, Nematodirus spp. inhibited L4, Oesophagostomum radiatum, Oesophagostomum spp. inhibited L4, Ostertagia leptospicularis, Ostertagia lyrata, Ostertagia ostertagi, Ostertagia spp. inhibited L4, Trichostrongylus axei, Trichostrongylus colubriformis, Trichostrongylus spp. inhibited L4, Trichuris discolor, and Trichuris ovis. Over the 120-day grazing period, Eprinomectin ERI-treated cattle gained between 4.8 kg and 31 kg more weight than the controls. This weight gain advantage was significant (p<0.05) in three studies. All animals accepted the treatment well. No adverse reaction to treatment was observed in any animal in any study.

Persistent efficacy and production benefits following use of extended-release injectable eprinomectin in grazing beef cattle under field conditions.

Seven studies were conducted in commercial grazing operations to confirm anthelmintic efficacy, assess acceptability, and measure the productivity response of cattle to treatment with eprinomectin in an extended-release injectable formulation (ERI) when exposed to nematode infected pastures for 120 days. The studies were conducted under one protocol in the USA in seven locations (Arkansas, Idaho, Louisiana, Minnesota, Missouri, Oregon, and Wisconsin). Each study had 67-68 naturally infected animals for a total of 475 (226 female, 249 male castrate) Angus or beef-cross cattle. The animals weighed 133-335 kg prior to treatment and were approximately 3-12 months of age. The studies were conducted under a randomized block design based on pre-treatment body weights to sequentially form 17 replicates of four animals each within sex in each study. Animals within a replicate were randomly assigned to treatments, one to Eprinomectin ERI vehicle (control) and three to Eprinomectin ERI (5%, w/v eprinomectin). Treatments were administered at 1 mL/50 kg body weight once subcutaneously anterior to the shoulder. All animals in each study grazed one pasture throughout the observation period of 120 days. Cattle were weighed and fecal samples collected pre-treatment and on 28, 56, 84, and 120 days after treatment for fecal egg and lungworm larval counts. Positive fecal samples generally were cultured en masse to determine the nematode genera attributable to the gastrointestinal helminth infection. Bunostomum, Cooperia, Haemonchus, Nematodirus, Oesophagostomum, Ostertagia, and Trichostrongylus, when present, were referred to as strongylids. At all post-treatment sampling intervals, Eprinomectin ERI-treated cattle had significantly (P<0.05) lower strongylid egg counts than vehicle-treated controls, with ≥95% reduction after 120 days of grazing. Over this same period, Eprinomectin ERI-treated cattle gained more weight (43.9 lb/head) than vehicle-treated controls in all studies. This weight gain advantage was significant (P<0.05) in six of the studies with the Eprinomectin ERI-treated cattle gaining an average of 42.8% and the control cattle gaining 33.1% of their initial weight. No adverse reactions were observed in the treated animals.

An eprinomectin extended-release injection formulation providing nematode control in cattle for up to 150 days

A series of 10 dose confirmation studies was conducted to evaluate the persistent activity of an extended-release injectable (ERI) formulation of eprinomectin against single point challenge infections of gastrointestinal and pulmonary nematodes of cattle. The formulation, selected based on the optimal combination of high nematode efficacy, appropriate plasma profile, and satisfactory tissue residue levels, includes 5% poly(D,L-lactide-co-glycolic)acid (PLGA) and is designed to deliver eprinomectin at a dose of 1.0mg/kg bodyweight. Individual studies, included 16-30 cattle blocked based on pre-treatment bodyweight and randomly allocated to treatment with either ERI vehicle or saline (control), or the selected Eprinomectin ERI formulation. Treatments were administered once at a dose volume of 1 mL/50 kg bodyweight by subcutaneous injection in front of the shoulder. In each study, cattle were challenged with a combination of infective stages of gastrointestinal and/or pulmonary nematodes 100, 120 or 150 days after treatment and were processed for parasite recovery according to standard techniques 25-30 days after challenge. Based on parasite counts, Eprinomectin ERI (1mg eprinomectin/kg bodyweight) provided >90% efficacy (p<0.05) against challenge with Cooperia oncophora and Cooperia surnabada at 100 days after treatment; against challenge with Ostertagia ostertagi, Ostertagia lyrata, Ostertagia leptospicularis, Ostertagia circumcincta, Ostertagia trifurcata, Trichostrongylus axei, and Cooperia punctata at 120 days after treatment; and against challenge with Haemonchus contortus, Bunostomum phlebotomum, Oesophagostomum radiatum and Dictyocaulus viviparus at 150 days after treatment. Results of a study to evaluate eprinomectin plasma levels in cattle treated with the Eprinomectin ERI formulation reveal a characteristic second plasma concentration peak and a profile commensurate with the duration of efficacy. These results confirm that the Eprinomectin ERI formulation can provide high levels of parasite control against a range of nematodes of cattle for up to 5 months following a single treatment.

Evaluation of a barrier dental sealant in dogs.

A study was conducted in 40 healthy, randomly selected, client-owned, mixed and purebred dogs to assess the efficacy of a barrier dental sealant. All dogs showed evidence of dental plaque, calculus, or gingivitis. The dental sealant was applied to one side of the mouth following a professional teeth cleaning procedure and reapplied weekly for 8-weeks following the cleaning procedure. Dental parameters evaluated included plaque, calculus, gingivitis, and gingival bleeding indices. A statistically significant difference was detected between treated and untreated teeth compared with baseline values for plaque and calculus at weeks 4 and 8, gingivitis at week 4, and gingival bleeding time at week 8. A professional teeth cleaning procedure followed by a single application of the barrier dental sealant and weekly reapplication performed by a veterinarian or veterinary technician provided significant improvement in plaque and calculus indices during an 8-week period.

Assessment of the onset of action of afoxolaner against existing adult flea (Ctenocephalides felis) infestations on dogs.

The speed of kill of afoxolaner against experimental infestations by Ctenocephalides felis was evaluated after oral administration of afoxolaner in a soft chew (NEXGARD(®)) at a dose to achieve 2.5mg/kg bodyweight. Forty beagles were allocated to two treatment groups. Dogs in Treatment Group 1 were untreated controls. Dogs in Treatment Group 2 were treated on Day-0 with afoxolaner, according to their pre-treatment bodyweight. All dogs were infested with approximately 100 C. felis on Day-1. Live fleas were counted upon removal at 5 time points after treatment (i.e., 2, 4, 8, 12 and 24h after treatment). For each time point, counts were performed on 4 dogs from each of the treated and the untreated groups. Early curative flea killing efficacy was evaluated with respect to the untreated control group. The afoxolaner treated group had significantly fewer fleas than the untreated control group at 8, 12, and 24h (p<0.001). The percent efficacies of orally administered afoxolaner were 15.0%, 87.8%, 99.5%, 100.0%, and 100.0% at 2, 4, 8, 12, and 24h, respectively. In this study, afoxolaner began killing fleas by 2h after treatment with increasing efficacy at subsequent time points and had >99.5% efficacy at 8, 12, and 24h after treatment demonstrating an early onset of action.