Objective—To identify biomarkers of P-glycoprotein (P-gp) substrate neurotoxicity in transgenic mice expressing the mutant canine ABCB1 gene (ABCB1-1Δ). Animals—8 ABCB1 knock-in and knock-out transgenic mice expressing the ABCB1-1Δ gene and 8 control mice expressing the wild-type canine ABCB1 gene (ABCB1-WT). Procedures—Groups including 2 ABCB1-1Δ mutant mice and 2 ABCB1-WT mice were administered the P-gp substrates ivermectin (10 mg/kg, SC), doramectin (10 mg/kg, SC), moxidectin (10 mg/kg, PO), or digoxin (1.53 mg/kg, SC). A toxicogenomic approach based on DNA microarrays was used to examine whole-genome expression changes in mice administered P-gp substrates. Results—Compared with control ABCB1-WT mice, ABCB1-1Δ mutant mice developed neurotoxic signs including ataxia, lethargy, and tremors similar to those reported for dogs with the ABCB1-1Δ mutation. Microarray analysis revealed that gene expression was altered in ABCB1-1Δ mutant mice, compared with findings for ABCB1-WT mice, following administration of the same P-gp substrates. Gene pathway analysis revealed that genes with a ≥ 2-fold gene expression change were associated with behavior and nervous system development and function. Moreover, 34 genes were altered in the ABCB1-1Δ mutant mice in all 4 drug treatment groups. These genes were also associated with behavior, which was identified as the top-ranked gene network. Conclusions and Clinical Relevance—These study data have facilitated understanding of the molecular mechanisms of neurotoxicosis in ABCB1-1Δ mutant mice following exposure to various P-gp substrates. Some genes appear to be potential biomarkers of P-gp substrate neurotoxicity that might be used to predict the safety of those drugs in dogs with the ABCB1-1Δ mutation.

Objective--To evaluate the nematocidal effectiveness of the ivermectin sustained-release bolus throughout its 135-day delivery period. Design--Twenty-four naturally infected calves were randomly allocated to 1 of 3 equivalent experimental groups: group-T1 calves were untreated controls, group-T2 calves each received a sustained-release bolus on trial day 0 and group-T3 calves were rendered nematode-free and used at 35-day intervals during the study as tracers. One contaminated pasture was used for all principal calves for the 135-day grazing interval of the study. Calves of groups T1 and T2 were also artificially administered mixed infective nematode larvae at intervals during the grazing period, after which, all calves were confined to concrete for 21 days prior to necropsy. Animals--All calves were approximately 6 months old on trial day 0, weighed from 136 to 216 kg, and were of mixed breeding and sex. Procedure--At intervals during the study, feces from all calves were analyzed for nematode egg counts, and all calves were weighed and examined for bolus retention (T2 calves only). For nematode recovery, all calves were necropsied 21 to 22 days after removal from the contaminated pasture. Results--Parasitic populations of Haemonchus, Ostertagia, Trichostrongylus, Cooperia, Bunostomum, and Oesophagostomum spp were significantly reduced in cattle treated with the ivermectin sustained-release bolus. Conclusion--The nematocidal activity of the ivermectin sustained-release bolus proved highly effective, with > 98% efficacy for all nematode species present.

Efficacy of abamectin against gastrointestinal tract nematodes and lungworms of cattle was determined in 4 experiments. The first 2 experiments were controlled trials in which efficacy was determined at necropsy in calves with either experimentally induced (n = 14) or naturally acquired (n = 16) infections. Half the calves in each experiment were treated with abamectin (200 micrograms/kg of body weight, sc), and half were left untreated as controls. Efficacy was > 99% against adult stages of Dictyocaulus viviparus, Haemonchus placei, Ostertagia ostertagi, Trichostrongylus axei, Cooperia punctata, Trichuris discolor, and C oncophora, and was 92.4% against Nematodirus helvetianus. The second 2 experiments were clinical trials in which efficacy was determined by fecal egg count reduction in naturally infected yearling heifers (n = 75) or 2-year-old heifers (n = 75). Within replicates of 5, 4 heifers were assigned at random to treatment with 200 Kg of abamectin/kg and 1 was left untreated as a control. Abamectin was 100% effective in eliminating strongylate nematode eggs from the feces of these heifers. In all experiments, adverse reactions were limited to small, clinically unimportant injection site swellings in 29% of abamectin-treated calves. Abamectin was judged to be safe and effective in these trials.

The efficacy of a beef-based, chewable formulation of ivermectin against a mixed infection of Ancylostoma braziliense and A tubaeforme was determined in cats. Ivermectin administered orally at approximately 24 microgram/kg of body weight was 92.8% effective against adult A braziliense and 90.7% effective against adult A tubaeforme. The number of eggs per gram of feces had decreased 98.1% by 7 days after treatment. Clinical signs of hookworm disease also decreased after treatment. Location of adult parasites within the small intestine, percentage of infecting larvae that developed to the adult stage, and egg size in cats with infections of A braziliense and A tubaeforme were similar to those reported for cats with separate infections of either species.

To assess the effect of ivermectin on immune function (antibody production), male CD-1 mice were inoculated with an antigen the day after SC administration of ivermectin (0.2 mg/kg of body weight or 20 mg/kg). Responses were evaluated 5 days after inoculation of the antigen. Antibody production against sheep RBC, a T lymphocyte-, macrophage-dependent response, was enhanced by ivermectin treatment (P = 0.00049). In contrast, antibody production against dinitrophenyl-Ficoll, a T lymphocyte-independent, macrophage-dependent response, was not altered by ivermectin treatment. Results indicate that the immunostimulatory properties of ivermectin are associated with altered function of T lymphocytes, in particular, T-helper lymphocytes. The immunomodulating effects of ivermectin may provide an alternative approach for treatment of disease problems involving immunosuppression.

Twelve Holstein calves mere used to determine the prophylactic efficacy of ivermectin against challenge exposure with gastrointestinal and pulmonary nematodes. Two groups of 6 calves (mean body weight, 205 kg) each were formed by restricted randomization according to body weight. Group-l calves served as nonmedicated controls. Each calf of group 2 was orally given one prototype sustained-release bolus designed to deliver ivermectin at a continuous daily dose of 8 mg. Third-stage nematode infective larvae were given to the calves on posttreatment days 28 and 42. The calves were euthanatized 77 or 78 days after treatment. Ivermectin was 100% effective (P < 0.05) in preventing the establishment of infection by Haemonchus placei, Ostertagia ostertagi, Cooperia spp (C punctata, C oncophora, C surnabada), Nematodirus helvetianus, Oesophagostomum radiatum, and Dictyocaulus viviparus and was > 99% effective against Trichostrongylus axei. Incidental infection by Trichuris spp was reduced by 94% (P = 0.08).

The efficacy of a single dose of ivermectin (0.2 mg/kg), in injectable or paste formulations, against microfilariae of Onchocerca cervicalis and associated skin lesions was evaluated in 20 naturally infected horses during midsummer months in Louisiana. All horses had clinical signs of dermatitis of the ventral midline and/or limbs, shoulders, thorax, and withers. Efficacy was monitored at 21, 42, and 63 days after treatment. Procedures done at these intervals included microfilarial counts of 6-mm skin biopsy specimens of affected ventral midline, grading of gross lesions, and photography and histologic assessment of ventral midline biopsy specimens. Microfilarial numbers were reduced to 0 by 21 days after treatment in all but one horse. Active lesions improved or were resolved completely by 63 days after treatment. Total inflammation, as judged by histologic methods, was reduced in all horses by 63 days after treatment, but there was a residual population of inflammatory cells in all horses. Adverse reactions after treatment were not observed in any of the horses.

gastrointestinal nematodes, calves (exper.), efficacy of ivermectin given subcutaneously or given orally as drench or paste

The activity of ivermectin against common nematode parasites of sheep was examined in 2 experiments. In the 1st experiment, 14 sheep with naturally acquired infections were assigned to 2 groups of 7 sheep each. Sheep in 1 group were treated with 200 micrograms of ivermectin/kg of body weight and the remainder served as nontreated controls. In the 2nd experiment, 15 sheep with experimentally supplemented infections (including a benzimidazole-resistant strain of Haemonchus contortus) were assigned to 3 groups of 5 each. The 1st group was treated with 200 micrograms of ivermectin/kg, the 2nd was treated with 88 mg of thiabendazole/kg, and the 3rd served as nontreated controls. Ten to 12 days after treatment, all sheep were euthanatized and necropsied, and the parasites they harbored were recovered and identified. Efficacy of ivermectin was excellent (greater than 96%) against Dictyocaulus filaria, H contortus, Ostertagia circumcinta, Marshallagia marshalli, Trichostrongylus axei, T colubriformis, and T vitrinus. Treatment was not as uniformly effective for Nematodirus spathiger (73% to 85%), N filicollis (80% to 96%), Cooperia curticei (92% to 100%), immature nematodes (92% to 100%), and early 4th-stage larvae (46% to 100%). Efficacy of thiabendazole was poor for H contortus (42%) and early 4th-stage larvae in the abomasum (52%), but approached 100% for most of the other parasites.

Psoroptes ovis, calves, control with ivermectin, dosages and routes of administration; effect on Bovicola bovis; Otobius megnini not affected