Melbourne Veterinary School - Research Publications

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    Mathematical modeling and simulation in animal health. Part III: Using nonlinear mixed-effects to characterize and quantify variability in drug pharmacokinetics
    Bon, C ; Toutain, PL ; Concordet, D ; Gehring, R ; Martin-Jimenez, T ; Smith, J ; Pelligand, L ; Martinez, M ; Whittem, T ; Riviere, JE ; Mochel, JP (WILEY, 2018-04-01)
    A common feature of human and veterinary pharmacokinetics is the importance of identifying and quantifying the key determinants of between-patient variability in drug disposition and effects. Some of these attributes are already well known to the field of human pharmacology such as bodyweight, age, or sex, while others are more specific to veterinary medicine, such as species, breed, and social behavior. Identification of these attributes has the potential to allow a better and more tailored use of therapeutic drugs both in companion and food-producing animals. Nonlinear mixed effects (NLME) have been purposely designed to characterize the sources of variability in drug disposition and response. The NLME approach can be used to explore the impact of population-associated variables on the relationship between drug administration, systemic exposure, and the levels of drug residues in tissues. The latter, while different from the method used by the US Food and Drug Administration for setting official withdrawal times (WT) can also be beneficial for estimating WT of approved animal drug products when used in an extralabel manner. Finally, NLME can also prove useful to optimize dosing schedules, or to analyze sparse data collected in situations where intensive blood collection is technically challenging, as in small animal species presenting limited blood volume such as poultry and fish.
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    Effect of distal ulnar ostectomy on carpal joint stability during weight bearing in the dog
    Amsellem, PM ; Young, AN ; Muirhead, TL ; Pack, L ; Moak, P ; Matthews, AR ; Marcellin-Little, DJ (WILEY, 2017-11-01)
    OBJECTIVE: To assess the influence of a 50% distal ulnectomy on mediolateral carpal stability in the dog. STUDY DESIGN: Canine cadaveric study. SAMPLE POPULATION: Seven canine thoracic limbs METHODS: Thoracic limbs were placed in a jig to mimic weight bearing with a load representing 30% of body weight. Carpal extension angle was standardized at 190° ± 5°. Frontal plane carpal angles were measured with the limb loaded on craniocaudal radiographs before and after ulnectomy. Valgus and varus stress radiographs with the limb loaded were acquired before and after ulnectomy. The limbs were palpated and were subjectively graded for valgus or varus instability by 2 investigators before and after ulnectomy. RESULTS: Mean (±SD) valgus angulation increased after ulnectomy (2.1° ± 1.7°; P = .017; CI95  = 0.5°-3.7°) when the limb was loaded without valgus or varus stress applied. Mean valgus angulation increased after ulnectomy (2.7° ± 2.8°; P = .032; CI95  = -0.2°-5.5°) when valgus stress was applied to the loaded limb. Varus angulation was unchanged after ulnectomy (0.6° ± 4.6°; P = .383; CI95  = -4.2°-5.3°) when varus stress was applied to the loaded limb. Palpation detected increased valgus score after ulnectomy. CONCLUSION: Distal ulnectomy with excision of the lateral styloid process induces a slight increase in valgus in canine cadaver carpi. The clinical consequences of that valgus on carpal function and health should be assessed in clinical patients.
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    Determination of testosterone esters in the hair of male greyhound dogs using liquid chromatography-high resolution mass spectrometry
    Devi, JL ; Zahra, P ; Vine, JH ; Whittem, T (WILEY, 2018-03-01)
    The doping of greyhound dogs with testosterone is done in an attempt to improve their athletic performance, but such doping cannot easily be confirmed, especially in male dogs owing to the natural presence of endogenous testosterone. As testosterone is usually administered as its esters, their direct detection in hair would provide confirmatory evidence of the administration of a pharmaceutical product. This article demonstrates that the use of a liquid chromatography-high resolution mass spectrometry method with heated electrospray ionisation (HESI) combined with the use of amino solid-phase extraction (SPE) cartridges for sample clean-up, is suitable for the sensitive determination of propionate, phenyl propionate, isocaproate, decanoate, and enanthate esters of testosterone in greyhound hair. The method is linear over the range, 0.1 μg/kg-10 μg/kg, for all the testosterone esters analysed. The limits of detection (LOD) are 0.05 μg/kg for testosterone phenyl propionate, isocaproate, and decanoate, 0.025 μg/kg for testosterone propionate, and 0.25 μg/kg for testosterone enanthate. This method was applied to hair samples collected from male greyhounds before and after a single administration of a product containing several testosterone esters, each of which could be detected up to 100 days post-administration. The study also demonstrates that tail hair is the specimen of choice for the analysis of testosterone in dog hair and that washing of dogs does not impact the analysis of testosterone esters in hair. This method may be useful in racing regulation for the detection of illegitimate use of testosterone in all species.
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    Retrospective evaluation of cats with elapid snake envenomation associated neurotoxicity requiring mechanical ventilation: 12 cases (2005-2014)
    Ong, HM ; Kelers, K ; Hughes, D ; Boller, M (WILEY, 2017-09-01)
    OBJECTIVE: To retrospectively determine the population and outcome characteristics of a cohort of Australian elapid snake envenomed cats requiring mechanical ventilation (MV). DESIGN: Retrospective observational study (2005-2014). SETTING: Academic veterinary emergency and critical care service. ANIMALS: Twelve cats undergoing MV for elapid snake envenomation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The medical records were searched to identify cats requiring MV as part of treatment for elapid snake envenomation. Signalment, the indication for, duration of and complications associated with MV, duration of hospitalization, and survival to hospital discharge were recorded for each of the enrolled cases. Seven cats (58.3%) underwent MV because of presumed unsustainable respiratory effort and 5 cats (41.7%) for respiratory arrest. Eleven cats (91.7%) were successfully weaned from MV and survived to hospital discharge. No cats developed ventilator associated pneumonia or pneumothorax. The median duration of MV was 19.5 hours for the survivors (range 7.0-37.0 hours) and median duration of hospitalization was 3.5 days (range 2.4-14.9 days). CONCLUSIONS: Cats requiring MV for elapid snake envenomation have a favorable outcome and require a relatively short period of MV. Complications encountered are unlikely to influence outcome.
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    Chemical stability of morphine and methadone, and of methadone in combination with acepromazine, medetomidine or xylazine, during prolonged storage in syringes
    Lee, DY ; Watson, N ; Whittem, T (WILEY, 2017-08-01)
    OBJECTIVE: To assess the chemical and physical stability of morphine and methadone stored in syringes for 12 months and of methadone when mixed with acepromazine, medetomidine or xylazine. METHODS: A high-performance liquid chromatography (HPLC) technique was developed and validated for the analysis of morphine and methadone. Morphine and methadone were dispensed into syringes and stored at 25°C/60% relative humidity (RH) and 40°C/75% RH. Solutions containing mixtures of methadone combined with acepromazine, medetomidine or xylazine were stored in syringes at 25°C/60%RH. At initiation, after 1 week and then 1, 3, 6, 9 and 12 months, samples were analysed by HPLC for the quantification of the morphine or methadone. Measured concentrations were assessed as a function of storage time and temperature using linear regression statistics to calculate stability. RESULTS: When stored at 40°C/75%RH as pre-dispensed syringes, severe physical and chemical changes were observed after the third month for both morphine and methadone. In contrast, at 25°C/60%RH both drugs remained chemically stable for 12 months, with concentration variations not exceeding a 5% change from initiation as stipulated in VICH stability guidelines. When in combination with acepromazine or xylazine, methadone also remained chemically stable, but the combination with medetomidine failed stability criteria prior to 6 months. Precipitation compromised the physical stability of methadone in all unsealed syringes prior to 9 months' storage. CONCLUSION: Pre-dispensing morphine or methadone into unsealed syringes compromises the drugs' physical stability. Mixing of methadone with other drugs can degrade its chemical stability.
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    Impact of diet on faecal output and caecotroph consumption in rabbits
    Meredith, AL ; Prebble, JL (WILEY, 2017-01-01)
    OBJECTIVES: To assess the impact of four rabbit diets (hay only, extruded diet with hay, muesli with hay and muesli only) on faecal pellet size, faecal output and caecotrophy. MATERIALS AND METHODS: Thirty-two Dutch rabbits were studied over 17 months. Faecal pellet size and weight were measured in weeks 3, 9, 21 and 43 and faecal output in weeks 10, 22 and 45. Number of uneaten caecotrophs was recorded weekly. RESULTS: Faecal pellets were consistently smaller and lighter in rabbits fed muesli only, and the size of pellets produced by those fed muesli with hay decreased over the course of the study. Faecal output was greatest in rabbits with the highest hay intake. Uneaten caecotrophs were found in greatest frequency in rabbits fed muesli. CLINICAL SIGNIFICANCE: Muesli diets have a negative effect on faecal output and caecotroph ingestion and may therefore predispose to digestive disorders. Higher hay intake is associated with greater faecal output and fewer uneaten caecotrophs and may assist in preventing the gastrointestinal stasis.
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    Evidence for marsh mallow (Malva parviflora) toxicosis causing myocardial disease and myopathy in four horses
    Bauquier, J ; Stent, A ; Gibney, J ; Jerrett, I ; White, J ; Tennent-Brown, B ; Pearce, A ; Pitt, J (Wiley, 2017-05-01)
    REASON FOR PERFORMING THE STUDY: Investigation of toxicosis caused by Malva parviflora was required after 4 horses from the same farm developed severe muscle fasciculations, tachycardia, sweating and periods of recumbency leading to death or euthanasia after ingesting the plant. OBJECTIVES: To describe historical, clinical, clinicopathological and pathological findings of 4 horses with suspected M. parviflora toxicosis. The role of cyclopropene fatty acids (found in M. parviflora) and mechanism for toxicosis are proposed. STUDY DESIGN: Case series. METHODS: Historical, physical examination, clinicopathological and pathological findings are reported. Due to similarities with atypical myopathy or seasonal pasture myopathy acyl carnitine profiles were performed on sera from 2 cases and equine controls. Presence of cyclopropene fatty acids was also examined in sera of 2 cases. RESULTS: M. parviflora had been heavily grazed by the horses with little other feed available. Horse 1 deteriorated rapidly and was subjected to euthanasia. Horse 2 was referred to hospital where severe myocardial disease and generalised myopathy was determined; this horse was subjected to euthanasia 36 h after admission. Horse 3 died rapidly and Horse 4 was subjected to euthanasia at onset of clinical signs. Post-mortem examinations performed on 3 horses revealed acute, multifocal cardiac and skeletal myonecrosis. Myocyte glycogen accumulation was absent when examined in Horse 2. Acyl carnitine profiles revealed increased C14-C18 acyl carnitine concentrations in cases relative to controls. Cyclopropene fatty acids were detected in sera of cases but not controls. CONCLUSION: These findings suggest aetiology different to that of atypical myopathy or seasonal pasture myopathy. We hypothesise that cyclopropene fatty acids in M. parviflora interfere with fatty acid β-oxidation in horses in negative energy balance, causing the clinical signs and abnormal acyl carnitine profiles. These equine cases suggest a pathophysiological course that closely mimics the human genetic condition very long chain acyl CoA dehydrogenase deficiency.
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    The cardiopulmonary effects and quality of anesthesia after induction with alfaxalone in 2-hydroxypropyl-beta-cyclodextrin in dogs and cats: a systematic review
    Chiu, KW ; Robson, S ; Devi, JL ; Woodward, A ; Whittem, T (WILEY, 2016-12-01)
    To systematically review the quality of evidence comparing the cardiopulmonary effects and quality of anesthesia after induction with alfaxalone vs. other anesthetic agents in dogs and cats. Studies published from 2001 until 20th May 2013 were identified with the terms 'alfaxan' OR 'alfaxalone' OR 'alphaxalone' in electronic databases: Discovery, PubMed, ScienceDirect, and Wiley Interscience. The study design and risk of bias of all included studies were assessed. Twenty-two studies from 408 (22 of 408, 5.39%) satisfied the inclusion criteria. Fourteen studies (14 of 22, 64%) focused on dogs and nine (9 of 22, 40%) on cats. One study had both dogs and cats as subjects. (Hunt et al., 2013) Twelve studies were rated an LOE1, and six of these as ROB1. One, seven, and two studies were rated as LOE2, LOE3, and LOE5, respectively. In dogs, strong evidence shows that induction quality with either alfaxalone-HPCD or propofol is smooth. Moderate evidence supports this finding in cats. In dogs, moderate evidence shows that there is no significant change in heart rate after induction with either alfaxalone-HPCD or propofol. In cats, moderate evidence shows no significant difference in postinduction respiratory rate and heart rate between alfaxalone-HPCD and propofol induction. Strong evidence shows dogs and cats have smooth recoveries after induction using either alfaxalone-HPCD or propofol, before reaching sternal recumbency.
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    Utstein-style guidelines on uniform reporting of in-hospital cardiopulmonary resuscitation in dogs and cats. A RECOVER statement
    Boller, M ; Fletcher, DJ ; Brainard, BM ; Haskins, S ; Hopper, K ; Nadkarni, VM ; Morley, PT ; McMichael, M ; Nishimura, R ; Robben, JH ; Rozanski, E ; Rudloff, E ; Rush, J ; Shih, A ; Smarick, S ; Tello, LH (WILEY-BLACKWELL, 2016-01-01)
    OBJECTIVE: To provide recommendations for reviewing and reporting clinical in-hospital cardiopulmonary resuscitation (CPR) events in dogs and cats and to establish nonambiguous operational definitions for CPR terminology. DESIGN: Consensus guidelines. SETTING: International, academia, referral practice, general practice, and human medicine. METHODS: An international veterinary Utstein task force was convened in April 2013 in San Francisco to determine the scope of the project, the variables to be reported, their definitions, and a reporting template. Factors that were essential for meaningful data reporting and were amenable to accurate collection (ie, core variables) and additional variables useful for research projects and hypothesis generation (ie, supplemental variables) were defined. Consensus on each item was either achieved during that meeting or during the subsequent online modified Delphi process and dialogue between task force members. RESULTS: Variables were defined and categorized as hospital, animal, event (arrest), and outcome variables. This report recommends a template for standardized reporting of veterinary in-hospital CPR studies involving dogs or cats. Core elements include the suspected cause(s) and location of arrest, first rhythm identified, the occurrence of return of spontaneous circulation (ROSC) of more than 30 seconds (any ROSC) or more than 20 minutes (sustained ROSC), survival to discharge, and functional capacity at discharge. If CPR is discontinued or the patient is euthanized by owner request, a reason is reported. The task force suggests a case report form to be used for individual resuscitation events. CONCLUSIONS: The availability of these veterinary small animal CPR reporting guidelines will encourage and facilitate high-quality veterinary CPR research, improve data comparison between studies and across study sites, and serve as the foundation for veterinary CPR registries.
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    Bovine digital dermatitis in Victoria, Australia.
    Hesseling, J ; Legione, AR ; Stevenson, MA ; McCowan, CI ; Pyman, MF ; Finochio, C ; Nguyen, D ; Roic, CL ; Thiris, OL ; Zhang, AJ ; van Schaik, G ; Coombe, JE (Wiley, 2019-10-01)
    AIMS: The objectives of this study were to estimate the prevalence of digital dermatitis (DD) in Victoria, Australia, and to investigate which organisms are consistent with typical DD lesions. The prevalence and causative pathogens of DD are not clear yet in Australia and this paper is one of the first to explore these questions in this country. METHODS: Examination and sampling of limbs was undertaken at three knackeries in Victoria, Australia. Limbs were classified as normal (N), active DD-lesion (A), dried or chronic DD-lesion (D) or suspected case of DD (S). A total of 823 cows were examined. Six skin biopsies were taken at each knackery, from which DNA was extracted for diversity profiling. Histochemical staining of samples was performed on eight of the skin biopsies. RESULTS: DD was detected in 29.8% of all cows. The prevalence of DD was significantly higher in dairy cows (32.2%) than in beef cows (10.8%). The differential abundance of Treponema-species was significantly increased in dried lesions, compared with the normal skin biopsies. Actinobacteria, Proteobacteria, Firmicutes and Tenericutes were found to be significantly different in abundance in the DD lesions compared with normal skin biopsies. Silver staining of samples showed only mild inflammation and in two samples organisms with morphology consistent with Spirochaetes were detected. CONCLUSIONS: The calculated prevalence indicates that DD is present in Victoria, Australia. The results of diversity profiling showed that the presence of Treponema-species was significantly different between the samples of DD lesions and normal skin.