Influence of gastrointestinal tract disease on pharmacokinetics of lidocaine after intravenous infusion in anesthetized horses

OBJECTIVE: To determine the disposition of lidocaine after IV infusion in anesthetized horses undergoing exploratory laparotomy because of gastrointestinal tract disease. ANIMALS: 11 horses (mean +/- SD, 10.3 +/- 7.4 years; 526 +/- 40 kg). PROCEDURE: Lidocaine hydrochloride (loading infusion, 1.3 mg/kg during a 15-minute period [87.5 microg/kg/min]; maintenance infusion, 50 microg/kg/min for 60 to 90 minutes) was administered IV to dorsally recumbent anesthetized horses. Blood samples were collected before and at fixed time points during and after lidocaine infusion for analysis of serum drug concentrations by use of liquid chromatography-mass spectrometry. Serum lidocaine concentrations were evaluated by use of standard noncompartmental analysis. Selected cardiopulmonary variables, including heart rate (HR), mean arterial pressure (MAP), arterial pH, PaCO2, and PaO2, were recorded. Recovery quality was assessed and recorded. RESULTS: Serum lidocaine concentrations paralleled administration, increasing rapidly with the initiation of the loading infusion and decreasing rapidly following discontinuation of the maintenance infusion. Mean +/- SD volume of distribution at steady state, total body clearance, and terminal half-life were 0.70 +/- 0.39 L/kg, 25 +/- 3 mL/kg/min, and 65 +/- 33 minutes, respectively. Cardiopulmonary variables were within reference ranges for horses anesthetized with inhalation anesthetics. Mean HR ranged from 36 +/- 1 beats/min to 43 +/- 9 beats/min, and mean MAP ranged from 74 +/- 18 mm Hg to 89 +/- 10 mm Hg. Recovery quality ranged from poor to excellent. CONCLUSIONS AND CLINICAL RELEVANCE: Availability of pharmacokinetic data for horses with gastrointestinal tract disease will facilitate appropriate clinical dosing of lidocaine.     

Stress-related behaviors among horses used in a therapeutic riding program

OBJECTIVE: To determine whether therapeutic riding resulted in higher levels of stress or frustration for horses than did recreational riding and whether therapeutic riding with at-risk individuals was more stressful for the horses than was therapeutic riding with individuals with physical or emotional handicaps. DESIGN: Observational study. ANIMALS: 14 horses in a therapeutic riding program. PROCEDURE: An ethogram of equine behaviors was created, and horses were observed while ridden by 5 groups of riders (recreational riders, physically handicapped riders, psychologically handicapped riders, at risk children, and special education children). Number of stress-related behaviors (ears pinned back, head raised, head turned, head tossed, head shaken, head down, and defecation) was compared among groups. RESULTS: No significant differences in mean number of stress-related behaviors were found when horses were ridden by recreational riders, physically handicapped riders, psychologically handicapped riders, or special education children. However, mean number of stress-related behaviors was significantly higher when horses were ridden by the at-risk children. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that for horses in a therapeutic riding program, being ridden by physically or psychologically handicapped individuals is no more stressful for the horses than is being ridden in the same setting by recreational riders. However, at-risk children caused more stress to the horses, suggesting that the time horses are ridden by at-risk children should be limited both daily and weekly.     

Effects of a therapeutic riding program on at-risk and special education children

OBJECTIVE: To determine the effects of a therapeutic riding program on psychosocial measurements among children considered at risk for poor performance or failure in school or life and among children in special education programs. DESIGN: Observational study. POPULATION: 17 at-risk children (6 boys and 11 girls) and 14 special education children (7 boys and 7 girls). PROCEDURE: For the at-risk children, anger, anxiety, perceived self-competence, and physical coordination were assessed. For the special education children, anger and cheerfulness were measured, and the children's and their mothers' perceptions of the children's behavior were assessed. Measurements were made before and after an 8-session therapeutic riding program. RESULTS: For boys enrolled in the special education program, anger was significantly decreased after completion of the riding program. The boys' mothers also perceived significant improvements in their children's behavior after completion of the program. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that an 8-session therapeutic riding program can significantly decrease anger in adolescent boys in a special education program and positively affect their mothers' perception of the boys' behavior.     

Hemodynamic effects in dogs after intramuscular administration of a combination of dexmedetomidine-butorphanol-tiletamine-zolazepam or dexmedetomidine-butorphanol-ketamine

Objective-To evaluate hemodynamic effects in dogs after IM administration of dexmedetomidine (7.5 μg/kg, butorphanol (0.15 mg/kg), and tiletamine-zolazepam (3 mg/kg [DBTZ]) or dexmedetomidine (15 μg/kg), butorphanol (0.3 mg/kg), and ketamine (3 mg/kg [DBK]). Animals-5 healthy adult mixed-breed dogs. Procedures-Each dog received DBTZ and DBK in a randomized crossover study with a 48-hour interval between treatments. Anesthesia was induced and maintained with sevoflurane in 100% oxygen while instrumentation with Swan-Ganz and arterial catheters was performed. Following instrumentation, hemodynamic measurements were recorded at 3.54% (1.5 times the minimum alveolar concentration) sevoflurane; then sevoflurane administration was discontinued, and dogs were allowed to recover. Six hours after cessation of sevoflurane administration, baseline hemodynamic measurements were recorded, each dog was given an IM injection of DBTZ or DBK, and hemodynamic measurements were obtained at predetermined intervals for 70 minutes. Results-DBTZ and DBK induced hypoventilation (Paco(2), approx 60 to 70 mm Hg), respiratory acidosis (pH, approx 7.2), hypertension (mean arterial blood pressure, approx 115 to 174 mm Hg), increases in systemic vascular resistance, and reflex bradycardia. Cardiac output, oxygen delivery, and oxygen consumption following DBTZ or DBK administration were similar to those following sevoflurane administration to achieve a surgical plane of anesthesia. Blood l-lactate concentrations remained within the reference range at all times for all protocols. Conclusions and Clinical Relevance-In healthy dogs, both DBTZ and DBK maintained oxygen delivery and oxygen consumption to tissues and blood lactate concentrations within the reference range. However, ventilation should be carefully monitored and assisted when necessary to prevent hypoventilation.     

Antithrombotic Therapy

Thrombosis or thromboembolism are significant concerns in companion animals and can be associated with cardiac, metabolic, neoplastic disease processes or can be one manifestation of inflammatory, infectious, and neoplastic disease conditions. Options for thromboprophylaxis available for clinical use in small animal patients are very limited, with heparin (primarily unfractionated, but more recently low-molecular-weight forms) and aspirin predominating. Controlled studies evaluating the use of these drugs are few, but there is some limited evidence for efficacy in prevention of formation of thrombi. Use of the vitamin K antagonist warfarin has been described, but the narrow therapeutic window has resulted in a high rate of serious adverse events. In human patients, the efficacy of aspirin, heparins, and vitamin K antagonists is well documented in a variety of thrombotic conditions, but there are significant limitations to each of these options. These limitations have prompted the search for new alternatives, some of which are now in wide clinical use in humans. Although the use of some of the drugs discussed here has not yet been described in veterinary patients at risk for thrombosis, many of these agents have been evaluated experimentally in dogs, cats, or both. These new thromboprophylactic agents may soon be beneficial in management of small animal patients at risk for thrombosis.     

Characterization of In Vitro Synthesized Equine Metabolites of the Selective Androgen Receptor Modulators S24 and S4

Several selective androgen receptor modulators (SARMs) have been synthesized and investigated in humans, rats, and dogs in the past, but no data are yet available concerning the metabolism of SARMs in horses. The aryl-propionamide-derived drug candidates S24 and S4 (andarine) have a strong androgen receptor binding affinity and show distinctive specific cell answers. Although no SARM drug candidate (aiming for testosterone replacement therapy) has completed clinical trials yet, S4 has been illicitly available via the Internet. These facts led to the prohibition of SARMs by the German equestrian federation, and the (mis)use of such compounds would further represent a doping rule violation in horse racing. In this study, the drug candidates S24 and S4 were subjected to in vitro metabolism experiments with equine liver microsomal preparations from a female Quarter Horse to obtain information about potential target analytes in equine doping control analysis. The enzymatically synthesized metabolites were characterized by liquid chromatography–tandem mass spectrometry and –high-resolution/high-accuracy mass spectrometry. All observed S24 and S4 equine metabolites are in agreement with earlier in vitro and in vivo studies in humans and dogs. Nevertheless, the relative percentage of generated equine metabolites (as determined from the analytes’ response in full-scan chromatography–tandem mass spectrometry and –high-resolution/high-accuracy mass spectrometry measurements) differs considerably from the reported profiles. Although the S24 metabolite pattern is comparably balanced concerning glucuronidated and sulfonated conjugates, the major S4 metabolite was found to be the unconjugated dephenylated compound, with a proportion of more than 90%.     

Canine corneal fibroblast and myofibroblast transduction with AAV5

Objective The aims of this study were (1) to determine the efficacy of adeno‐associated vector serotype 5 (AAV5) for delivering gene therapy to canine corneal fibroblasts (CCFs) and myofibroblasts (CCMs) using enhanced green fluorescent protein (GFP) marker gene and (2) to evaluate the cytotoxicity of AAV5 to CCFs and CCMs using an in vitro model. Methods Healthy donor canine corneas were used to generate primary CCFs by growing cultures in minimal essential medium supplemented with 10% fetal bovine serum. Canine corneal myofibroblasts were produced by growing cultures in serum‐free medium containing transforming growth factor β1 (1 ng/mL). An AAV5 titer (6.5 × 10¹² μg/mL) expressing GFP under control of hybrid cytomegalovirus + chicken β‐actin promoters (AAV5‐gfp) was used to transduce CCF and CCM cultures. Delivered gene expression in CCFs and CCMs was quantified using immunocytochemistry, fluorescent microscopy, and real‐time PCR. Transduction efficacy of the AAV5 vector was determined by counting DAPI‐stained nuclei and EGFP‐positive cells in culture. Phase‐contrast microscopy, trypan blue, and dUTP nick end labeling (TUNEL) assays were used to determine the toxicity and safety of AAV5 in this canine corneal model. Results Topical AAV5 application successfully transduced a significant population of CCFs (42.8%; P < 0.01) and CCMs (28%; P < 0.01). Tested AAV5 did not affect CCF or CCM phenotype or cellular viability and did not cause significant cell death. Conclusions The tested AAV5 is an effective and safe vector for canine corneal gene therapy in this in vitro model. In vivo studies are warranted.     

Circulatory, respiratory and behavioral responses in isoflurane anesthetized llamas

Objectives To evaluate the circulatory, respiratory and behavioral effects of isoflurane (ISO) anesthesia in llamas during mechanical ventilation and spontaneous breathing. Design Prospective randomised study. Animals Six adult, neutered male llamas (10 ± 1 years [mean ± SD], 179 ± 32 kg). Materials and methods Animals in which the minimum alveolar concentration (MAC) had been previously determined were anesthetized with ISO in oxygen. Inspired and end‐tidal (ET) ISO were sampled continuously. Arterial blood pH, respiratory and circulatory variables, and clinical signs of anesthesia were recorded at three doses (1.0, 1.5 and 2.0 times the individual animal's MAC; mean MAC value 1.13%) of ISO during spontaneous and controlled ventilation. A series of Latin squares was used to determine order of dose. Controlled ventilation (CV) (target PaCO₂ 38 ± 5 mm Hg [5.0 ± 0.6 kPa]) preceded spontaneous ventilation (SV) at each dose. Animals breathed spontaneously for approximately 10 minutes prior to data collection. Body temperature was maintained at 37 ± 0.6 °C. Circulatory and respiratory data were analysed with a mixed model, least squares analysis of variance, for repeated measures taken at equally spaced intervals. p < 0.05. Results Dose and mode of ventilation had significant influences on measured variables. For example, heart rate increased as dose increased; 67 ± 14 beats minute^?1 at 1.0 MAC‐CV versus 77 ± 6 beats minute^?1 at 2 MAC‐CV. Conversely, mean arterial pressure decreased with increasing dose; 82 ± 13 mm Hg at MAC‐CV versus 52 ± 15 mm Hg at 2 MAC‐CV. Arterial CO₂ increased with increasing dose during SV; 45 ± 5 mm Hg [6 ± 0.6 kPa] at MAC versus 53 ± 4 mmHg [7 ± 0.5 kPa] at 2 MAC. Reflex activity (e.g. palpebral reflex) and muscle tone (e.g. jaw tone) decreased while eyelid aperture increased with increasing anesthetic dose. Conclusions and Clinical Relevance The influence of ISO dose and mode of ventilation on circulatory and respiratory variables in llamas is qualitatively similar to that reported in other species. Changes in reflex activity and muscle tone may be used to guide appropriate anesthetic delivery in ISO‐induced llamas.