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Daphnée Veilleux-Lemieux,1,2 Francis Beaudry,1 Pierre Hélie,3 Pascal Vachon11Department of Veterinary Biomedicine, University of Montreal, Saint-Hyacinthe, 2Department of Veterinary Services, Laval University, Quebec, 3Department of Pathology and Microbiology, University of Montreal, Saint-Hyacinthe, CanadaPurpose: To evaluate the effects of endotoxemia on the pharmacokinetics and pharmacodynamics of ketamine and xylazine anesthesia in Sprague–Dawley rats.Methods: Sprague–Dawley rats received ketamine (80 mg/kg) and xylazine (5 mg/kg) intramuscularly following the intraperitoneal administration of different lipopolysaccharide concentrations (1, 10, and 100 µg/kg) to simulate different levels of endotoxemia. Results were compared to control animals receiving saline intraperitoneally. During anesthesia, a toe pinch was performed to evaluate anesthesia duration, and selected physiological parameters (heart and respiratory rates, oxygen saturation, and rectal temperature) were taken. Blood samples were also taken during anesthesia at selected time points for the analysis of plasmatic ketamine and xylazine concentrations by liquid chromatography–mass spectrometry. Blood samples were taken 1 week prior to and 24 hours following anesthesia for blood biochemistry.Results: Anesthesia duration significantly increased for moderate (10 µg/kg) and high (100 µg/kg) lipopolysaccharide groups. Liver histopathology showed minor to moderate necrosis in all lipopolysaccharide groups in some animals. The most important physiological change that occurred was a decrease in oxygen saturation, and for blood biochemistry a decrease in serum albumin. Ketamine pharmacokinetics were not affected except for the moderate (10 µg/kg) lipopolysaccharide group where a decrease in the area under the plasma concentration–time curve from time zero to the last measurable concentration, a decrease in half-life, and an increase in the clearance were observed. For xylazine, the area under the plasma concentration–time curve increased and the clearance decreased in the moderate (10 µg/kg) and high (100 µg/kg) lipopolysaccharide groups.Conclusion: During ketamine–xylazine anesthesia, endotoxemia may alter xylazine pharmacokinetics and selected biochemical and physiological parameters, suggesting that anesthetic drug dosages could be modified for a more rapid recovery.Keywords: lipopolysaccharide, ketamine, xylazine, pharmacokinetics, rats

In this study, we injected morphine sulfate IP into rainbow trout and measured the concentration of morphine and all potential metabolites in plasma using LC-MS/MS at a series of times after the injection. The pharmacokinetics of morphine were similar to those previously reported for seawater-acclimated rainbow trout, i.e. they were about one order of magnitude slower than in similarly sized mammals. The only metabolite of morphine present in the plasma was morphine-3-β-d-glucuronide (M3G); morphine-6-β-d-glucuronide (M6G) was not detected. M3G gradually increased after the morphine injection, peaked about 2 days later, then gradually decreased. In mammals, M3G plasma levels exceed morphine levels extremely rapidly, i.e. in less than an hour, regardless of dose, route of administration, or species. In trout, it took 2 days for M3G levels to exceed morphine levels. This is the first study of the metabolites of morphine in any ectotherm. We conclude that trout can metabolize morphine, but at a rate much slower than in mammals. [ABSTRACT FROM AUTHOR]

The objectives of this in vitro study were to describe cytochrome-dependent metabolism of clomipramine in canine and feline microsomes, compare metabolic profiles between cats, rats and dogs, and investigate a potential gender-related difference in metabolic activity between male and female cats. Pooled liver microsomes were incubated with clomipramine, where species and gender-specific reactions were initiated by the addition of a nicotinamide adenine dinucleotide phosphate regenerating system and quenched with methanol at 0, 5, 15, 30, 45 and 60 min, and 0, 30, 60, 90, 120, 180, 240 and 360 min respectively. Liquid chromatography tandem mass spectrometry was used to measure clomipramine and its metabolites. Preliminary results showed that cat microsomes biotransformed clomipramine slower and less efficiently than rat and dog microsomes. Moreover, gender differences in metabolic profiles suggested that male cat microsomes may be less efficient demethylators and hydroxylators than female cat microsomes. As gender metabolic differences may carry clinical significance for this antidepressant, further studies are warranted. [ABSTRACT FROM AUTHOR]

This study was conducted to confirm an interindividual variability in pharmacokinetic parameters of clomipramine in a large population of cats and to identify potential covariables that would explain the presence of such pharmacokinetic variability after a single dose of Clomicalm®. Clomipramine hydrochloride was administered orally according to a weight-dose chart from 0.32 to 0.61 mg/kg, to 76 cats and five blood samples were then taken by direct venipuncture at 1, 3, 6, 12, and 24 h. Plasma concentrations of clomipramine and desmethylclomipramine (DCMP) were measured by LC-MS/MS. The Standard Two-Stage technique was used to assess differences and detect correlations between pharmacokinetic parameter estimates and individual covariables. A large interindividual variability in all pharmacokinetic parameters (CV% 64–124) was detected. Statistically significant gender-related differences were detected in MR and Cl/ F, where female cats had a higher mean MR (0.53) and faster Cl/ F (0.36 L/h·kg) than males (0.36 and 0.21 L/h·kg, respectively). No correlation could be found between clomipramine AUC0-24h or DCMP AUC0-24h and sedation scores. Further feline studies are required to assess these findings after multiple dosing of clomipramine and DCMP to allow clinical extrapolation. [ABSTRACT FROM AUTHOR]

Eugenol, the principle chemical constituent of clove oil, has recently been evaluated for its anesthetic and analgesic properties in fish and amphibians. The objective of this study was to determine the pharmacokinetic (PK) and anesthetic activity of eugenol in rats. Male Sprague–Dawley rats received single i.v. doses of eugenol (0, 5, 10, 20, 40 and 60 mg/kg) and anesthetic level was evaluated with the withdrawal reflex. For the 20 mg/kg dose level, blood and urinary samples were collected over 1 h for the PK assessment. Plasma and blood concentrations of eugenol, as well as metabolite identification in urine, were determined using a novel dansyl chloride derivatization method with liquid chromatography mass spectrometry (LC/MS/MS). PK parameters were calculated using noncompartmental methods. Eugenol-induced loss of consciousness in a dose-dependent manner, with mean (±SEM) recovery in reflex time of 167 ± 42 sec observed at the highest dose level. Mean systemic clearance ( Cl) in plasma and blood were 157 and 204 mL/min/kg, respectively. Glucuronide and sulfate conjugates were identified in urine. Overall, eugenol produced a reversible, dose-dependent anesthesia in male Sprague–Dawley rats. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of amoxycillin was studied in nine male beagle dogs under healthy and febrile conditions. In Period 1, dogs received 20 mg/kg of an oral suspension of amoxycillin. Intravenous doses of saline, 2 and 20 μg/kg of endotoxin (LPS from Escherichia coli serotype) were administered to dogs (three per group) prior to administration of 20 mg/kg of amoxycillin in Period 2. Rectal temperature and behavioral changes were recorded and blood samples were collected over 12 h for pharmacokinetic analysis. Amoxycillin was assessed in plasma using liquid chromatography coupled with mass spectrometry. Plasma concentrations were analysed using a one-compartment model with lag-time for absorption using an iterative two-stage method. As compared with control groups, amoxycillin clearance decreased significantly with preliminary treatments of 2 μg/kg endotoxin (0.209 vs. 0.140 L/h kg, P < 0.05) and 20 μg/kg endotoxin (0.214 vs. 0.075 L/h kg, P < 0.05). As a result of this, the area under curve for the 2 and 20 μg/kg endotoxin groups increased significantly 100.4 vs. 149.4 μg h/mL (P < 0.05) and 99.2 vs. 277.7 μg h/mL (P < 0.05), respectively. Other drugs currently used for the treatment of fever and septic shock should be re-evaluated using a febrile animal model to avoid improper dose administration. [ABSTRACT FROM AUTHOR]

The article examines the impact of static and dynamic compression on bone growth and quality during growth modulation using a rat tail model. Topics mentioned include the way the mechanical loading and device implantation affect the mean growth rate (GR), reduction in the quality of the newly formed bone due to device implantation, and the similarity of GR reduction induced by static and dynamic compression.

Few studies have verified the validity of behavioral and physiological methods of pain assessment in cattle. This prospective, blinded, randomized controlled experimental study aimed to validate different methods of pain assessment during acute and chronic (up to 21 d postintervention) conditions in dairy cattle, in response to 3 analgesic treatments for traumatic reticuloperitonitis. Cerebrospinal fluid (CSF) biomarkers and mechanical sensitization were measured as indicators of centralized pain. Proteomics in the CSF were examined to detect specific (to pain intensity) and sensitive (responsive to analgesia) markers. Recordings of spontaneous behavior with video analysis, telemetered motor activity, pain scales, electrodermal activity, and plasma cortisol concentration were quantified at regular intervals. Cows were assigned to group 1 (n = 4, standard control receiving aspirin), group 2 (n = 5, test group receiving preemptive tolfenamic acid), or group 3 (n = 3, positive control receiving preemptive multimodal analgesia composed of epidural morphine, plus tolfenamic acid and butorphanol). Rescue analgesia was administered as needed. Generalized estimating equations tested group differences and the influence of rescue analgesia on the measurements. All 3 groups demonstrated a long-term decrease in a CSF protein identified as transthyretin. The decrease in transthyretin expression inversely correlated with the expected level of analgesia (group 1 < 2 < 3). Moreover, in group 1, CSF noradrenaline decreased long term, cows were hypersensitive to mechanical stimulation, and they demonstrated signs of discomfort with higher motor activity and "agitation while lying" recorded from video analysis. Decreased "feeding behavior," observer-reported pain scales, electrodermal activity, and plasma cortisol concentration were inconsistent to differentiate pain intensity between groups. In summary, changes in CSF biomarkers and mechanical sensitization reflected modulation of central pain in dairy cows. The spontaneous behavior "agitation while lying" was the only behavioral outcome validated for assessing acute and chronic pain in this visceral pain model. [ABSTRACT FROM AUTHOR]