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- Author or Editor: Michael J. Myers x
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Abstract
Objective—To determine whether there is a relationship between species-specific mitochondrial DNA (mtDNA), especially canine and feline mtDNA, and detectable amounts of pentobarbital in previously analyzed dog food samples.
Sample Population—31 dog food samples previously analyzed for pentobarbital (limit of detection, 1 µg/kg).
Procedure—Polymerase chain reaction (PCR) analysis was performed on dog food samples by use of PCR primers specific for either canine, feline, equine, bovine, porcine, ovine, or poultry mtDNA.
Results—PCR amplicons specific for feline or canine mtDNA at a 0.007% (70 µg/g [wt/wt basis]) or 0.0007% (7 µg/g) level, respectively, were not found in the 31 dog food samples. Most of the 31 dog food samples had a PCR amplicon on PCR analysis when a PCR primer set capable of simultaneously detecting mtDNA of cows, pigs, sheep, goats, deer, elk, and horses was used. Results of PCR analysis by use of primers specific for bovine, swine, sheep and goat, or horse mtDNA revealed amplicons specific for bovine or swine mtDNA only in 27 of the 31 samples. Analysis of the remaining 4 samples failed to yield amplicons for any mammalian mtDNA. Pentobarbital was detected in 2 of these 4 samples. Results of PCR analysis correlated with the stated ingredient list for most, but not all samples.
Conclusions and Clinical Relevance—Because canine and feline mtDNA were not found in a set of retail dog food samples, these results indicate that the source of pentobarbital in dog food is something other than proteins from rendered pet remains. ( Am J Vet Res 2004;65:99–103)
Abstract
Objective
To determine whether recombinant porcine somatotropin (PST) or chromium picolinate (CrP) affected cytokine production and metabolism in swine after endotoxin challenge exposure.
Animals
20 Poland China × Landrace pigs, 5/group.
Procedure
Pigs were given CrP-supplemented feed at body weight of 20 kg; PST treatment began at 60 kg, and both treatments continued through body weight of 90 kg. At 90 kg, pigs were challenge exposed with 20 μg of lipopolysaccharide (LPS)/kg of body weight. Blood samples were obtained at various times through 24 hours after LPS challenge exposure.
Results
In all pigs not given PST, glucose concentration decreased 2 to 4 hours after LPS. In PST-treated pigs, blood glucose concentration was decreased at 6 to 8 hours after LPS. Plasma insulin concentration paralleled changes in glucose concentration. Nonesterified fatty acid concentration was high 2 to 24 hours after LPS in pigs not given PST and at 6 to 24 h in PST-treated pigs. Plasma urea nitrogen concentration was high at 6 to 24 hours after LPS in pigs not given PST. The urea nitrogen values in PST-treated pigs were lower at all times. Serum aspartate transaminase activity was high 6 to 24 hours after LPS in pigs not given PST, whereas PST treatment prevented the increase in this enzyme activity. In untreated (PST) pigs, plasma bilirubin (total and direct) concentrations were high 4 to 8 hours after LPS and returned to normal at 24 hours. The PST- and CrP-treated pigs maintained normal plasma bilirubin concentrations. Interleukin 6 activity was unaffected by CrP and PST treatments. Treatment with CrP and PST decreased the tumor necrosis factor α response to LPS, compared with that in control pigs.
Conclusions
PST, and to a lesser extent CrP, provide protection against the adverse metabolic effects of LPS-induced septic shock. (Am J Vet Res 1997;58: 594–600)
Abstract
Objective—To determine the effect of oral administration of low doses of pentobarbital on cytochrome P450 (CYP) isoforms and CYP-mediated reactions in immature Beagles.
Animals—42 immature (12-week-old) Beagles.
Procedure—Dogs were grouped and treated orally as follows for 8 weeks: low-dose pentobarbital (50 µg/d; 4 males, 4 females), mid-dose pentobarbital (150 µg/d; 4 males, 4 females), high-dose pentobarbital (500 µg/d; 4 males, 4 females), positive-pentobarbital control (10 mg/kg/d; 2 males, 2 females), positivephenobarbital control (10 mg/kg/d; 2 males, 2 females), and negative control (saline [0.9% NaCl] solution; 5 males, 5 females). Serum biochemical and hematologic values were monitored. On necropsy examination, organ weights were determined, and histologic evaluation of tissue sections of liver, kidney, small intestine, testes, epididymis, and ovaries was performed. Hepatic and intestinal drug-metabolizing enzyme activities were measured, and relative amounts of CYP isoforms were determined by western blot analysis.
Results—The amount of a hepatic CYP2A-related isoform in dogs from the high-dose pentobarbital treatment group was twice that of dogs from the negative control group. CYP2C was not detectable in small intestinal mucosa of dogs from the negative control group; measurable amounts of CYP2C were found in dogs from the various (low-, mid-, and high-dose) pentobarbital treatment groups and from positive-pentobarbital and positive phenobarbital control groups. Several CYP-mediated reactions increased in a dosedependent manner. The lowest calculated effective dose of pentobarbital ranged from 200 to 450 µg/d.
Conclusions and Clinical Relevance—Several CYP isoforms and their associated reactions were induced in dogs by oral administration of low amounts of pentobarbital. (Am J Vet Res 2003;64:1167–1175)
Abstract
Objective—To investigate effects of bacteria-mediated inflammation on hepatic drug metabolizing enzymes (DMEs) in swine via a lipopolysaccharide (LPS) challenge technique.
Animals—22 Poland China–Landrace crossbred barrows.
Procedures—In experiment 1, 10 market-weight swine were treated with LPS (20 μg/kg, IV [n = 5 swine]) or sham-injected (5) 24 hours before slaughter. In experiment 2, 12 growing and finishing swine were treated with LPS at 2 or 20 μg/kg, IV (n = 3 swine/age group/treatment) 24 hours before slaughter. Hepatic DMEs, cytochrome P450 (CYP) isoforms, and CYP-mediated reactions were measured.
Results—In experiment 1, LPS administered at 20 μg/kg decreased most hepatic DME components and inhibited enzymatic activities. In experiment 2, both doses reduced protein content in subcellular fractions and inhibited some DME- and CYP-mediated activities. In growing and finishing swine, CYP2A and CYP2B isoforms were not detected after treatment with LPS; the CYP1A2 isoform was eliminated in growing but not in finishing swine. Lipopolysaccharide also reduced CYP2D6 content in growing and finishing swine but increased CYP2E content. Lipopolysaccharide had no effect on swine CYP2C11, CYP2C13, or CYP3A content. The CYP2B-mediated 7-pentoxyresorufin O-dealkylase activity in growing and finishing swine was totally eliminated, and 7-ethoxyresorufin (indicating CYP1A activity) and aniline (mediated by CYP2E) metabolism was decreased.
Conclusions and Clinical Relevance—Effect of LPS treatment on swine CYPs appeared to be isoform specific; age-related metabolic status of the swine and the LPS dose modified this effect. Lipopolysaccharide-induced inflammation may affect metabolism of drugs and xenobiotics in swine.
Abstract
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.
SUMMARY
The effect of oxytetracycline (otc) on bovine blood mononuclear cells and neutrophil functions was examined in vitro. Neutrophil functions tested include respiratory burst, peroxidase, and antibacterial activities. Neutrophils were treated with otc (10 to 1,500 μg/ml) before exposure to either opsonized zymosan or bacteria. A dose-response inhibition antibacterial activity to high concentrations of otc (500 to 1,000 μg/ml) was observed. Beginning at a concentration 15 μg/ml, otc treatment of neutrophil lysates resulted in decreased peroxidase activity. A dose response was not observed. In contrast, respiratory burst, measured by nitroblue tetrazolium dye reduction, increased after otc exposure, but only at high concentrations (500 and 1,000 μg/ml) of otc. Mitogen-induced proliferation of blood mononuclear cells cocultured with otc and concanavalin A, phytohemagglutinin-P, or pokeweed mitogen was inhibited at an otc concentration of 100 μg/ml at 48 and 72 hours of culture. These results indicate that blood mononuclear cells are more sensitive to the inhibitory effects of otc than are neutrophils. Furthermore, the otc-mediated inhibition of neutrophil antimicrobial activity is inversely related to the increase in nitroblue tetrazolium reduction. This suggests that otc is uncoupling the hexose monophosphate shunt from production of secreted oxygen radicals. These results also suggest that the peroxidase enzyme system has a large biological reserve capacity.
Abstract
OBJECTIVE
To describe an ultrasound-guided technique for central venous catheter placement via the external jugular vein (EJV) in pigs.
ANIMALS
96 healthy Landrace–Poland China barrows (approx 16 weeks old with a mean weight of 70 kg).
PROCEDURES
Pigs were anesthetized. With ultrasound guidance, a needle was inserted into the EJV without a large incision or cutdown procedure. A guidewire was inserted through the needle into the vein. A modified Seldinger technique was used to advance a catheter into the vessel until the tip was in the cranial vena cava near the right atrium. A trocar was used to create a tunnel through the subcutaneous tissues from the catheter insertion site to between the dorsal borders of the scapulae. The free end of the catheter was passed through that tunnel. An extension was attached to the catheter and secured to the skin. Pigs were euthanized and underwent necropsy at completion of the study for which they were catheterized.
RESULTS
Central venous catheters were successfully placed in all 96 pigs and facilitated collection of serial blood samples with minimal stress. Catheters remained in place for a mean of 6 days (range, 4 to 10 days). Necropsy revealed abscesses along the subcutaneous catheter tract in 9 pigs. Twenty pigs had histologic evidence of phlebitis and fibroplasia in the cranial vena cava.
CONCLUSIONS AND CLINICAL RELEVANCE
The described technique, in combination with extensive socialization, allowed serial collection of blood samples with minimal stress and restraint and is an alternative to surgical cutdown procedures for catheter placement. (Am J Vet Res 2021;82:760–769)
Abstract
Objective—To develop in genetically engineered mice an alternative screening method for evaluation of P-glycoprotein substrate toxicosis in ivermectin-sensitive Collies.
Animals—14 wild-type C57BL/6J mice (controls) and 21 genetically engineered mice in which the abcb1a and abcb1b genes were disrupted and the mutated canine ABCB1 gene was inserted.
Procedures—Mice were allocated to receive 10 mg of ivermectin/kg via SC injection (n = 30) or a vehicle-only formulation of propylene glycol and glycerol formal (5). Each was observed for clinical signs of toxic effects from 0 to 7 hours following drug administration.
Results—After ivermectin administration, considerable differences were observed in drug sensitivity between the 2 types of mice. The genetically engineered mice with the mutated canine ABCB1 gene had signs of severe sensitivity to ivermectin, characterized by progressive lethargy, ataxia, and tremors, whereas the wild-type control mice developed no remarkable effects related to the ivermectin.
Conclusions and Clinical Relevance—The ivermectin sensitivity modeled in the transgenic mice closely resembled the lethargy, stupor, disorientation, and loss of coordination observed in ivermectin-sensitive Collies with the ABCB1–1Δ mutation. As such, the model has the potential to facilitate toxicity assessments of certain drugs for dogs that are P-glycoprotein substrates, and it may serve to reduce the use of dogs in avermectin derivative safety studies that are part of the new animal drug approval process.
Abstract
Objective
To characterize factors that affect solid-phase gastric emptying in healthy cats by use of nuclear scintigraphy and to assess differences in emptying patterns of dry and canned diets.
Animals
20 healthy cats.
Procedure
2 groups of 10 cats each were fed dry or canned diet for at least 2 weeks before scintigraphy was done. Diets were labeled with 99mTc-disofenin. After ingestion of labeled meals, scintigraphic images were obtained at 0, 15, 30, 45, and 60 minutes, then every 30 minutes to 6 hours. Gastric emptying scans were obtained 3 times for each cat for each diet, in a complete crossover design. The T90, T50, and T20 (times when 90, 50, and 20% of initial meal activity remained in the stomach, respectively) were derived from gastric emptying curves fit to nonlinear models. A mixed models approach was used for data analysis.
Results
Gastric emptying was well described by a nonlinear model. Meal size, water intake, and diet type significantly (P < 0.05) effected gastric emptying. The T90, T50, and T20 increased with meal size, regardless of diet type or water intake. Gastric emptying of a dry diet meal took significantly (P < 0.05) longer than that of an isocaloric meal of canned diet, except when meal size was small. Differences in gastric emptying of dry and canned diets varied with the phase (T90 vs T50 vs T20) of emptying.
Conclusion
Water intake, meal size, and diet type significantly influence gastric emptying in healthy cats, and these factors must be considered in analysis of gastric emptying data. (Am J Vet Res 1998;59:388–392)
Objective
To compare tympanic membrane temperature readings obtained with 2 commercially available devices with rectal temperature readings obtained with a standard mercury thermometer in dairy cattle, dairy calves, and swine.
Design
Clinical trial.
Animals
6 Holstein calves (approx 6 months old), 6 Holstein cattle (approx 4 years old), and 5 Landrace-Poland China swine.
Procedure
Tympanic membrane temperatures were measured, and results were compared with rectal temperatures obtained with a standard mercury thermometer. Tympanic membrane temperatures were obtained before and after insertion of the rectal thermometer. Temperature readings in swine were obtained following passive restraint in a cage-like device or restraint using a snare to assess the effect of stress on tympanic membrane temperature.
Results
Tympanic membrane temperature readings from both devices were lower than those obtained using a rectal thermometer for all animals. Repeated measurement of tympanic membrane temperature of individual cattle resulted in consistent readings for both devices.
Clinical Implications
Because all animals were visibly healthy, results suggest that tympanic membrane temperature readings obtained with either device may be an adequate assessment of health status. (J Am Vet Med Assoc 1996;207:1700-1701)