Ability of an oral formulation of afoxolaner to protect dogs from Borrelia burgdorferi infection transmitted by wild Ixodes scapularis ticks.

A randomized, blinded, negative controlled study was conducted to determine whether treatment with afoxolaner (NexGard®, Merial, Inc.) would prevent the transmission of Borrelia burgdorferi to dogs by wild caught Ixodes scapularis ticks. Twenty healthy dogs were randomly assigned to two groups of ten dogs each. Ten dogs were treated orally on Day 0 at a dose near the minimum recommended dose of afoxolaner of 2.5mg/kg (actual doses 2.5-3.1mg/kg) and ten control dogs were not treated. On Day 28, each dog was infested with approximately 50 adult unfed wild caught I. scapularis that had a 67% B. burgdorferi infection rate (determined by polymerase chain reaction). On Day 33, live ticks were counted and removed. No ticks were found on treated dogs while control dogs had an average of 21.4 ticks. To detect infection, the B. burgdorferi-specific C6 antibody SNAP® 4Dx® test (IDEXX) was performed on serum collected before infestation (all dogs seronegative on Days -6 and 27) and on Days 48, 63, 77 and 92. The ten treated dogs remained seronegative through the end of the study (Day 92), while nine out of the ten control dogs were infected, as demonstrated by their seroconversion to being positive for the presence of the B. burgdorferi-specific C6 antibody starting on Day 48. In this study, all dogs treated with NexGard® 28days prior to challenge with wild caught I. scapularis ticks were protected from B. burgdorferi infection, while nine out of the ten untreated control dogs were infected.

Effects of L-749,329, an ET(A)/ET(B) endothelin receptor antagonist, in a porcine coronary artery injury model of vascular restenosis.

BACKGROUND: Previous studies in animal models of angioplasty have suggested a role in neointimal hyperplasia for endothelins (ETs), potent vasoconstricting peptides that also exert growth-promoting effects. The present studies were undertaken to test the hypothesis that endothelin receptor blockade can reduce neointimal thickening in injured porcine coronary arteries. METHODS AND RESULTS: An ET(A)/ET(B) antagonist, L-749,329, was evaluated as an inhibitor of intimal thickening in a porcine balloon/stent model of coronary artery injury. L-749,329 competitively inhibited [(125)I]ET-1 binding to porcine ET(A) (IC(50) approximately 0.3 nmol/L) or ET(B) (IC(50) approximately 20 nmol/L) receptors and inhibited ET-1-stimulated signaling in cell culture. In anesthetized pigs, big ET-1-stimulated increases in systemic blood pressure were totally inhibited after intravenous infusion of L-749,329 (>/=0.2 mg. kg(-1). h(-1)). In vascular injury studies, pigs were treated with vehicle or L-749,329 (1 mg. kg(-1). h(-1)) beginning 2 days before and continuing 28 days after experimental angioplasty. Left anterior descending, left circumflex, and/or right coronary arteries were injured by inflation of an angioplasty balloon wrapped with a coiled metallic stent. After 28 days, mean neointimal thickness in the L-749,329-treated group was reduced by 9.0% compared with vehicle-treated controls, but this effect was not statistically significant (P=0.13). CONCLUSIONS: Blockade of endothelin receptors for 28 days with only a mixed ET(A)/ET(B) receptor antagonist is insufficient to substantially inhibit intimal hyperplasia after balloon/stent coronary artery injury in the pig, in contrast to results with a selective ET(A) antagonist. The effects of selective or mixed ET(A)/ET(B) antagonists in diseased vessels remain to be determined in this model.

Evaluation of the effect of simulated rainfall on the efficacy of Ivomec Pour-On against Cooperia spp. infection in cattle.

Four controlled studies, one each in Australia, Germany, the United Kingdom, and the United States, involving 30 calves each were conducted to evaluate the effect of simulated rainfall on the efficacy of Ivomec Pour-On against infections of Cooperia spp. At 3 weeks before treatment the calves were infected orally with third-stage larvae of Cooperia spp. In each study a recent, locally derived field isolate was used. The calves were allocated by restricted randomization based on body weight within sex to one of the following treatments: unmedicated control with no rain, Ivomec Pour-On with no rain, Ivomec Pour-On with rain starting at 40 min before treatment, Ivomec Pour-On with rain starting at 10 min after treatment, and Ivomec Pour-On with rain starting at 60 min after treatment. Ivomec Pour-On was applied topically at a dose rate of 1 ml/10 kg body weight (500 microg ivermectin/kg body weight). The simulated rainfall was equivalent to a heavy shower of approximately 12.5 mm of water during a 30-min period. The calves were necropsied for worm counting at 14 or 15 days after treatment. An evaluation of the pooled data showed that as compared with the untreated controls, the Ivomec Pour-On-treated calves with no rain had significantly (P < 0.01) fewer C. oncophora (> 99%), C. punctata (> 99%), C. surnabada (> 98%), and combined Cooperia spp. (> 99%). The reduction in Cooperia numbers noted for calves exposed to simulated rainfall was > 96% for all Cooperia species, regardless of when the rainfall started relative to the application of Ivomec Pour-On. There was no significant (P > 0.1) difference between the Ivomec Pour-On-treated calves with no rain and the pooled groups with simulated rainfall or between the group with rain before treatment and the pooled groups with rain after treatment. Ivomec Pour-On was highly effective against established infections of Cooperia spp. when applied to wet animals or to animals becoming wet shortly after treatment.

Efficacy of an in-feed formulation of ivermectin against somatic larvae of Strongyloides ransomi in pregnant swine.

OBJECTIVE: To confirm that ivermectin fed for 7 days to pregnant sows controls transmission of Strongyloides ransomi larvae to pigs via the colostrum or milk. ANIMALS: 24 mixed-breed sows. PROCEDURE: The sows were infected with 250,000 S ransomi larvae on 3 occasions (days 63, 64, or 65, days 71 or 73, and days 78, 79, or 80 of gestation). Eight sows received ivermectin at a dosage of 100 micrograms of ivermectin/kg of body weight/d from days 92 to 99 of gestation, and 8 sows were treated from days 103 to 110 of gestation; 8 remaining sows received unmedicated vehicle. Numbers of S ransomi larvae were counted in samples of colostrum or milk collected 1, 2, and 7 days after parturition. At 7 and 14 days after parturition, fecal samples were collected from each sow and from 4 pigs from each litter for determination of nematode egg counts; at the latter date, pigs were euthanatized and necropsied for worm counting. RESULTS: Pigs born to ivermectin-treated sows had significantly (P < 0.01) fewer adult S ransomi than did those born to control sows; efficacy was 100%. Treated sows had significantly (P < 0.05) fewer S ransomi larvae in colostrum/milk samples taken 1, 2, and 7 days after parturition than did control sows; efficacy was 100%, with the exception of 1 S ransomi larva found in a milk sample from 1 treated sow at 2 days after parturition. CONCLUSION AND CLINICAL RELEVANCE: Ivermectin fed to sows during the last third of gestation at a dosage of 100 micrograms/kg/d for 7 consecutive days is highly efficacious for control of transmission of infective S ransomi larvae to pigs via colostrum or milk.

Nematocidal efficacy of eprinomectin, delivered topically, in naturally infected cattle.

OBJECTIVE: To assess the nematocidal efficacy of eprinomectin in naturally infected cattle. ANIMALS: 62 (31 eprinomectin-treated and 31 control) beef mixed-breed or Holstein cattle, either 6 to 11 or 48 to 96 months old. PROCEDURE: Cattle were housed 21 to 27 days before treatment to allow parasites to reach maturity. Animals were grouped by sex, ranked by weight, and randomly assigned to treatment group. Fecal flotation was done to identify cattle with intestinal nematode infections. Treatment groups were: 1--eprinomectin topical vehicle (1 ml/10 kg) and 2--eprinomectin topical solution (1 ml/10 kg). Cattle were euthanatized by replicate on day 14 or 15, and standard procedures were used to recover of pulmonary, abomasal, small intestinal, and large intestinal nematodes. RESULTS: Eprinomectin efficacy across all trials was 100% against adult Trichostrongylus axei, Haemonchus placei, Oesophagostomum radiatum, and Dictyocaulus viviparus, as well a fourth-stage larval Oes radiatum, Ostertagia ostertagi, Nematodirus helvetianus, and Cooperia spp. Efficacy against adult O ostertagi, Cooperia oncophora, C punctata, C surnabada, C spatulata, N helvetianus, Trichuris sp, and Trichuris fourth-stage larvae was 99.9 and 99.8, 99.6, 98.9, 98.3, 99.7, 97.8, and 84.3%, respectively. All results were significant (P < 0.01) except those for C spatulata. Adverse reactions were not observed. CONCLUSION AND CLINICAL RELEVANCE: Eprinomectin is a safe and effective nematocide against naturally acquired nematode infections in cattle when administered at a dosage of 500 micrograms/kg. Milk and meat withholding is not necessary when using this product.

An illustrated guide to endotracheal intubation in small non-human primates.

Endotracheal intubation allows precise delivery of inhaled anaesthetic agents. Intubation in small non-human primates (less than 1 kg), is straightforward, using commercially available equipment, and careful positioning of the animal. Equipment and methods are fully described and illustrated.

Nonpeptide glycoprotein IIb/IIIa inhibitors. 8. Antiplatelet activity and oral antithrombotic efficacy of L-734,217.

The antiplatelet activity of L-734,217, a nonpeptide platelet GPIIb/IIIa antagonist, was evaluated in the rat, guinea pig and dog. IC50 for inhibition of in vitro platelet aggregation for these species (agonists: adenosine diphosphate, collagen) were rat, 838,000 and > 1,100,000 nM; guinea pig, 124 and 156 nM; dog, 42 and 50 nM. In an in vivo rat/in vitro dog platelet aggregation assay, effective antiaggregatory plasma concentrations of L-734,217 were achieved after 8.0 to 16.0 mg/kg p.o. vs. 0.3 to 1.0 mg/kg i.v. to rats. Delays in platelet-dependent hemostatic plug formation in severed mesenteric arteries were observed after 2.0 to 5.0 mg/kg p.o. vs. 0.1 to 0.2 mg/kg i.v. to guinea pigs. Dose-dependent inhibitions of ex vivo platelet aggregation after 0.3 to 3.0 mg/kg p.o. and 0.03 to 0.3 mg/kg i.v. L-734,217 to conscious dogs yielded estimates of 8 to 16% oral bioavailability. The antiplatelet activity of 3.0 mg/kg p.o. L-734,217 in dogs was unaffected by dosage form or food. In a conscious dog model of left circumflex coronary artery electrolytic lesion, 3.0 mg/kg p.o. L-734,217 q4 to 8 hr reduced thrombus mass, prevented occlusive coronary artery thrombosis and reduced or prevented myocardial infarction and ventricular ectopy. In anesthetized dogs, a dissociation between inhibition of ex vivo platelet aggregation and template bleeding time prolongation was observed with i.v. L-734,217. The results of the coadministration of heparin, aspirin and L-734,217 to anesthetized dogs suggested a synergistic effect on template bleeding time with no effect on plasma L-734,217 concentrations. These findings indicate L-734,217 to be an important lead structure for the development of therapeutically useful oral antiplatelet agents.

Effects of subtype-selective and balanced angiotensin II receptor antagonists in a porcine coronary artery model of vascular restenosis.

BACKGROUND: Numerous studies have demonstrated the ability of angiotensin II (Ang II) receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors to inhibit intimal hyperplasia after balloon dilation of noncoronary arteries in small-animal models, suggesting an important role for Ang II in the response to injury. Although ACE inhibitors have not been similarly effective in nonhuman coronary models or in human restenosis trials, questions remain regarding the efficacy ACE inhibitors against tissue ACE and the contributions of ACE-independent pathways of Ang II generation. Unlike ACE inhibitors, Ang II receptor antagonists have the potential to inhibit responses to Ang II independent of its biosynthetic origin. METHODS AND RESULTS: In separate studies, three Ang II receptor antagonists, including AT1 selective (L-158,809), balanced AT1/AT2 (L-163,082), and AT2 selective (L-164,282) agents, were evaluated for their ability to inhibit vascular intimal thickening in a porcine coronary artery model of vascular injury. Preliminary studies in a rat carotid artery model revealed that constant infusion of L-158,809 (0.3 or 1.0 mg X kg-1 X d-1) reduced the neointimal cross-sectional area by up to 37% measured 14 days after balloon dilatation. In the porcine studies, animals were treated with vehicle or test compound beginning 2 days before and extending 28 days after experimental angioplasty. Left anterior descending, left circumflex, and/or right coronary arteries were injured by inflation of commercially available angioplasty balloons with placement of coiled metallic stents. Infusion of L-158,809 (1 mg X kg-1 X d-1), L-163,082 (1 mg X kg-1 X d-1), or L-164,282 (1.5 mg X kg-1 X d-1) in the study animals yielded plasma drug levels sufficient either to chronically block or, for L-164,282, to spare pressor responses to exogenous Ang II. Neither L-158,809, L-163,082, nor L-164,282 had statistically significant effects (P=.12, P=.75, and P=.48, respectively, compared with vehicle-treated controls) on neointimal thickness (normalized for degree of injury) measured by morphometric analysis at day 28 after angioplasty. CONCLUSIONS: These findings indicate that chronic blockade of Ang II receptors by either site-selective or balanced AT1/AT2 antagonists is insufficient to inhibit intimal hyperplasia after experimental coronary vascular injury in the pig. The results further suggest that, unlike in the rat carotid artery, Ang II is not a major mediator of intimal thickening in the pig coronary artery.

Hematologic values of captive Mexican wolves.

Hematologic reference values were determined for a captive population of 11 Mexican wolves (Canis lupus baileyi). Wolf pups from 4 to 24 weeks old had progressive age-related increases in PCV, hemoglobin concentration, mean cell volume, and RBC counts similar to those seen in domestic dog pups (C familiaris). Hematologic indices in wolves older than 24 weeks were comparable to those of the adult domestic dog; however, PCV, hemoglobin concentration, and RBC counts were higher.

Potential for localized, adjustable deep heating in soft-tissue environments with a 30-beam ultrasonic hyperthermia system.

Initial heating rates (degrees C/min) along parallel tracks at depths of 1-14 cm in a static, muscle-like phantom were determined from time-temperature profiles obtained with 'Helios', a 30-beam ultrasonic hyperthermia system developed by Varian Associates. Data were taken at a single operating frequency of 556 kHz, for different sets of focal plane ring diameters of the four-ring array applicator, different levels of transducer driving power and two different focal plane depths, 6 cm and 9 cm. In each experiment, at each point of temperature measurement, analysis of temperature versus time data over a 2 min heating interval permitted separation of the desired phantom heating from artefactual heating resulting primarily from absorption of transverse (shear) waves produced at phantom-metal probe catheter interfaces. The results of the studies conducted suggest that in a non-translating carriage mode, Helios can produce axially and laterally localized deep heating in soft tissues for tissue volumes of lateral dimension up to a minimum of 4 cm and tissue depths of at least 11 cm. The results obtained also suggest that Helios can produce laterally localized heating to tissue depths of at least 11 cm without excessive heating of superficial soft-tissue layers, for tissue volumes of lateral dimension up to a minimum of 8 cm. The methodology used in the phantom studies was applied to the production of localized heating in the right lobe of the liver of adult pigs. Temperature versus time profiles obtained in the in vivo studies indicated that, for the set of system parameters employed, concentration of ultrasonic power at greater depths in the liver (e.g. 10.5 cm versus 5 cm) could be achieved, suggesting that Helios should be able to produce localized heating of targeted hepatic volumes when its operating parameters are selected in accordance with effective treatment planning techniques.