Melbourne Veterinary School - Research Publications

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    Intravenous Acetaminophen Does Not Provide Adequate Postoperative Analgesia in Dogs Following Ovariohysterectomy
    Leung, J ; Beths, T ; Carter, JE ; Munn, R ; Whittem, T ; Bauquier, SH (MDPI, 2021-12)
    (1) Objective: To investigate the analgesic effects of intravenous acetaminophen after intravenous administration in dogs presenting for ovariohysterectomy. (2) Methods: 14 ASA I client-owned female entire dogs. In this randomized, blinded, clinical study, dogs were given meperidine and acepromazine intramuscularly before induction of anesthesia with intravenous propofol. Anesthesia was maintained with isoflurane in oxygen. Intravenous acetaminophen 20 mg/kg or 0.9% NaCl was administered postoperatively. Pain assessments were conducted using the Glasgow Pain Scale short form before premedication and at 10, 20, 60, 120, and 180 min post-extubation or until rescue analgesia was given. The pain scores, times, and incidences of rescue analgesia between the groups was compared. Blood was collected before and 2, 5, 10, 20, 40, and 80 min after acetaminophen administration. Acetaminophen plasma concentration was quantified by liquid chromatography-mass spectrometry. The acetaminophen plasma concentration at the time of each pain score evaluation was subsequently calculated. (3) Results: There was no significant difference in pain scores at 10 min, highest pain scores, or time of rescue analgesia between groups. In each group, 3 dogs (43%) received rescue analgesia within 20 min. (4) Conclusions: Following ovariohysterectomy in dogs, there was no detectable analgesic effect of a 20 mg/kg dosage of intravenous acetaminophen administered at the end of surgery.
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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)
    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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    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)
    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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    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)
    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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    The cardiopulmonary effects and quality of anesthesia after induction with alfaxalone in 2-hydroxypropyl-β-cyclodextrin in dogs and cats: a systematic review
    Chiu, KW ; Robson, S ; Devi, JL ; Woodward, A ; Whittem, T (WILEY, 2016-12)
    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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    The lower limit of quantification in pharmacokinetic analyses
    Woodward, A ; Whittem, T (Wiley, 2019-11-01)
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    A controlled randomized clinical trial to assess postoperative analgesia after thiopental-isoflurane anaesthesia or total intravenous anaesthesia with alfaxalone in dogs
    Bennell, PM ; Whittem, T ; Tudor, E (WILEY, 2019-05)
    Alfaxalone, a synthetic neuroactive steroid, has been attributed with properties including sedation, anaesthesia and analgesia. The clinical relevance of any analgesic properties of alfaxalone has not been demonstrated. This study was a prospective, blinded, randomized, negative control clinical trial in 65 healthy dogs presented for ovariohysterectomy. Anaesthesia was induced and maintained, for Group 1 (TIVA) dogs (n = 30) with intravenous alfaxalone alone and for Group 2 dogs (n = 35) with thiopental followed by isoflurane in 100% oxygen inhalation. After ovariohysterectomy, quantitative measures of pain or nociception were recorded at 15 min intervals for 4 hr using three independent scoring systems, a composite measure pain scale (CMPS), von Frey threshold testing and measures of fentanyl rescue analgesia. The mean CMPS scores of Group 2 (THIO/ISO) dogs remained higher than Group 1 (TIVA) dogs from 15 to 135 min post-surgery but this difference was not statistically significant. There were no significant differences between groups in the proportions of dogs requiring rescue fentanyl analgesia, the total fentanyl dose used or the time to first fentanyl dose. The Von Frey threshold testing was found to be unsuitable for measurement of pain in this experimental model. When administered as total intravenous anaesthesia, alfaxalone did not provide analgesia in the postoperative period.
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    Study design synopsis: Designing and performing pharmacokinetic studies for systemically administered drugs in horses
    Bermingham, E ; Davis, JL ; Whittem, T (WILEY, 2020-09)
    The goal of this editorial is to discuss best practice design, execution and reporting of a pharmacokinetic (PK) study in horses. Our target readers are clinicians who plan to perform this type of research, in a field, clinic or research setting but we also hope that this article might help readers of such work to appraise the articles and understand the quality of the studies. Our emphasis will be on appropriate study design and analytical method, drug and drug formulation choice and route of administration, animal choice, sample collection, storage and shipping, and reporting, rather than the PK data analysis itself.
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    Observations on the use of a pain numbing device for repetitive percutaneous sampling in sheep
    Munn, R ; Woodward, A ; Beths, T ; Whittem, T (WILEY, 2021-10)
    AIMS: To evaluate the success of a commercially available analgesic device (CoolSense; Coolsense Ltd, Tel Aviv, Israel) in ameliorating pain while sampling from subcutaneous tissue cages in sheep. METHODS: The CoolSense device was used as part of a major parent study involving repetitive percutaneous sampling of subcutaneous tissue cages in seven sheep. Sampling was performed by passing a hypodermic needle through the skin and withdrawing fluid from the tissue cage. Each sheep had 10 tissue cages that were individually sampled 14 times over 74 h. The device was placed on the skin of the sampling site immediately before sampling cooling and numbing the skin. The reaction of the sheep was observed by the operators, flinching or jumping as the needle was passed through the skin was deemed to be a failure. We recorded the success or failure of the device for each needle stick. This was opportunistic data collection as part of a pharmacokinetic trial, therefore no controls were included. RESULTS: A total of 1655 observations were recorded and then analysed using a generalised linear mixed model. Overall, 1380 of 1655 (83.4%) observations were recorded as successfully providing analgesia. Marked inter-occasion variability was noted with success ranging from 61.42% to 92.86% across sheep:period (approximately 140 observations each). As no controls were available, the effect of treatment could not be evaluated. CONCLUSIONS AND CLINICAL RELEVANCE: The CoolSense device is a viable option for veterinary research and clinical applications.
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    A randomised controlled masked clinical trial of two treatments for osteoarthritis in dogs
    Whittem, T ; Richards, L ; Alexander, J ; Beck, C ; Knight, C ; Milne, M ; Rockman, M ; Saunders, R ; Tyrrell, D (WILEY, 2021-07)
    The product 4CYTE™ Canine (Interpath Pty Ltd., Ballarat, Victoria, Australia) contains four active ingredients: three marine-derived ingredients and Epiitalis®, which is extracted from the seed of the plant Biota orientalis. Carprofen is a non-steroidal anti-inflammatory drug (NSAID) licensed for the treatment of osteoarthritis in dogs and is the active ingredient in several licensed products. This study aimed to compare the efficacy of 4CYTE Canine with carprofen for the treatment of pain from osteoarthritis. The trial was a randomised, masked, parallel group trial in dogs with naturally occurring osteoarthritis. Sixty-nine dogs with body weight of between 10 and 50 kg were enrolled in the study, of which 66 (95.7%) completed the study. The 4CYTE Canine was administered at 60 mg active/kg daily and carprofen at 2-4 mg/kg daily, with a loading dose of up to 4 mg/kg on the first day. The trial duration was 28 days. The primary outcome was defined as improvement in Owner Lameness Score at Day 28 compared with Day 0. Other outcomes measured included Veterinary Lameness Scores and the Owner Mobility Scores. At Day 28, 14 of 29 (48.3%) dogs that received 4CYTE Canine and 13 of 37 (35.1%) dogs that received carprofen had improved. The 4CYTE Canine was found to be non-inferior to carprofen at Day 14 for the Owner Mobility Score and at Day 28 for all three outcomes. This response pattern suggests that improvement in response to 4CYTE Canine continued between Days 14 and 28. These results support the conclusion that 4CYTE Canine is not inferior to carprofen by end-point clinical efficacy.