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Item Novel collagen-based wafers as a drug delivery method for local analgesia in deer antlers : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Veterinary Sciences at Massey University, Manawatu, New Zealand(Massey University, 2021) Sahebjam, FarzinIntroduction This study provided a practical and novel solution for post-operative pain mitigation and wound management after velvet antler removal in red deer (Cervus elaphus). Currently, there are no topical methods to mitigate pain for an extended period of time in deer following surgical removal of antlers. The current methods licensed in New Zealand provide only peri-operative analgesia with short-term effects and raise animal welfare concerns about whether animals are still in pain when the effect has worn off, especially in the deer industry in which a large number of animals are being managed. Materials and methods In vitro study: In vitro drug release test (IVDRT) was conducted using the Franz diffusion cell to assess the drug release rates of lidocaine and bupivacaine in two different phases of the pilot and main studies. The pilot in vitro study contained 9 treatment groups and 3 control groups (n=3), which were classified based on collagen extraction technique, whether modified with zinc oxide-polyvinylpyrrolidone (ZnO-PVP) nanoparticles and the difference in the order of adding local anaesthetics and ZnO-PVP nanoparticles. The main in vitro study was comprised of 4 treatment groups of 5%, 10%, and 25% ZnO-PVP nanoparticles (n=6) proportional to dry collagen weight and a control group. In both pilot and main in vitro studies, the samples were taken every 15 minutes in the first hour and every 2 hours up to 12 hours. LC-MS and HPLC were used for the quantification of the samples in the pilot and main in vitro studies, respectively. MNT validation study: Forty male deer (stags) were assigned for the MNT validation study on three alternative days. A handheld algometer (Wagner FPX50) was used for mechanical nociceptive threshold (MNT) assessment of four antler sites (cranial, medial, caudal, lateral) in both right and left antlers. Animal body weight (kg) and antler length (cm) were recorded to investigate the correlation with MNT. The MNT readings from three days were compared with each other. In addition, the MNT reading from all four antler sites and the right and left antlers were compared with each other. In vivo study: Eighteen stags sorted into three groups of 6 animals in each (2 treatment groups and 1 control group) for the pilot in vivo study, and forty yearling age stags assorted into four groups of 10 animals (three treatments and one control), were used in the main in vivo study. All animals had both antlers removed after administration of local anaesthesia. The control group in both pilot and main in vivo studies received a ring block of 4% articaine hydrochloride only, whilst the treatment groups received modified (with ZnO-PVP) or non-modified collagen composite wafers to the wound sites. The modified collagen composite wafers had 50% ZnO-PVP for the pilot in vivo study and had 0%, 5% or 25% ZnO-PVP proportional to dry collagen weight for the main in vivo study. A handheld algometer (Wagner FPX50), was used for mechanical nociceptive threshold (MNT) assessment at different time points (0, 4, 24, 72 hrs, 7 days and 14 days). Thermal imaging with a forward-looking infrared (FLIR) camera was performed for the detection of temperature differences between the groups. Digital photography of the wounds was performed for further quantitative wound healing analysis. Pharmacokinetic study: Blood samples were drawn from deer after the application of collagen composite wafers at time points t0, t1, t2, t4, t6, t8, t12, and t24 hours for the pilot study and at time points t0, t1, t2, t4, t6, t8, and t24 hours for the main in vivo study. The plasma was iv analysed with LC-MS to calculate pharmacokinetic parameters with the non-compartmental method such as Cmax, Tmax, AUC, AUMC, half-life, the volume of distribution and clearance. Statistical analysis: Higuchi model was mainly incorporated to calculate drug release rates for the in vitro studies. For in vivo studies, the statistical analyses were performed with a linear model for repeated measurements that accounted for the fixed effects of day, antler, location within antler or antler sites, antler length and weight of deer as covariates, and the random effect of animals. Results IVDRT did not show any statistically significant difference between the treatment groups; however, the treatment groups had significantly slower release compared to the control group in the pilot in vitro study. IVDRT in the main in vitro study showed the slowest release rate in the treatment group with 25% ZnO-PVP compared to the other groups for both lidocaine and bupivacaine. The control group had the most rapid drug release rates compared to the treatment groups, particularly for lidocaine. Furthermore, lidocaine showed a considerably slower release compared to bupivacaine when zinc oxide nanoparticles were incorporated, and the results significantly differed. MNT validation results showed that antler length (cm) and animal body weight (kg) are directly and positively correlated with the baseline MNT readings. The MNT readings from four sites of antlers, including cranial, medial, caudal and lateral aspects, did not have any significant difference from each other. In addition, the MNT readings from the right and left antlers did not show any significant difference from each other. In vivo results in the pilot study showed a lack of collagen composite wafer adherence for the non-modified wafers (PT2) and 50% adherence for the modified wafers (PT1) in the pilot study. As a result of the main in vivo study, 90%, 70%, and 45% were in group 25%NP (T1), 5%NP (T2), and 0%NP (T3) to the wounds, respectively. A significant difference was observed in the recovery rates of PT1 compared to the control group (P<0.0001) for the pilot study. For the main in vivo study, all three treatment groups also showed a significant difference compared to each other: T1 vs. T2 (P<0.01), T1 vs. T3 (P<0.05), and T2 vs. T3 (P<0.0001). In addition, the treatment groups showed a significantly slower recovery rate from analgesia compared to the control group (P<0.0001 for all). All the treatment groups in the main study demonstrated analgesia beyond 6 hrs and up to 10 hrs. The pharmacokinetics study showed significantly smaller Cmax for T1 and T2 compared to T3 only for bupivacaine. Tmax showed significantly smaller values for T1 compared to T2 for only bupivacaine. Both AUC (0-24), AUC (0-∞), and AUMC (0-∞) showed smaller values for T1 and T2 compared to T3. Conclusion The physically modified collagen composite wafer with zinc oxide-PVP nanoparticles, containing a short-acting (lidocaine) and a long-acting (bupivacaine) local anaesthetic, is a novel method to sustain drug delivery of local anaesthetics after the surgical removal of velvet antlers. Our suggested treatment can deliver analgesia to the wounded antler for up to 10 hours and is a safe and convenient method to use by farmers in the deer industry. Furthermore, the collagen wafer is very adhesive to the wound and can help facilitate wound healing of deer antlers.Item Efficacy of articaine hydrochloride for disbudding in goat kids and velvet antler removal in red deer, and novel disbudding methods for goat kids : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Veterinary Science at Massey University, Palmerston North, New Zealand(Massey University, 2019) Venkatachalam, DinakaranPainful husbandry procedures are routinely performed in farm animals all over the world. Most of these procedures can be humanely performed under local anaesthesia. Lignocaine is the most commonly used local anaesthetic in veterinary medicine. Even though lignocaine is a cheap and effective local anaesthetic, its use in goat kids and deer has been a concern. In goat kids, lignocaine has been reported to produce toxicity following cornual nerve block. In deer, the presence of lignocaine residue in the harvested velvet antlers following ring block has been a concern as one of its metabolites, 2,6-dimethylaniline (DMA) has been classified as a possible carcinogen in humans. Articaine hydrochloride is an amide-type local anaesthetic with unique pharmacological properties such as rapid hydrolysis in plasma to an inactive metabolite and high lipid solubility. It is widely used in humans for local and regional nerve blocks in dentistry. Several studies in humans suggested that articaine hydrochloride was effective and safer than lignocaine. Given concerns on the use of lignocaine in goat kids and deer, a series of studies were conducted to evaluate the safety and efficacy of articaine hydrochloride as an alternative to lignocaine hydrochloride for disbudding in goat kids and velvet antler removal in deer. As there is a paucity of data on the toxicity of lignocaine in goat kids, the thesis has also investigated the toxicity of lignocaine hydrochloride in goat kids. In addition, novel analgesic and disbudding techniques for goat kids were evaluated. The dose-ranging studies in goat kids suggested that doses up to 8 mg kg–1 and 7 mg kg–1 of articaine hydrochloride and lignocaine hydrochloride, respectively, can be safely used for perineural injections. Pharmacokinetic studies demonstrated that articaine hydrochloride was rapidly hydrolysed and eliminated in goat kids. The elimination half-life of articaine (1.26 ± 0.34 hours) was determined to be shorter than the elimination half-lives of lignocaine (1.71 ± 0.51 hours) and lignocaine’s metabolite, monoethylglycinexylidide (3.19 ± 1.21 hours) in goat kids. The total dose of articaine (16.24 ± 1.79 mg kg–1) required to produce convulsions in goat kids was higher than that of lignocaine (12.31 ± 1.42 mg kg–1). The mean convulsive plasma concentrations of articaine and lignocaine were 9.90 ± 2.38 µg mL–1 and 13.59 ± 2.34 µg mL–1, respectively. Both pharmacokinetic and toxicity data indicate that articaine has a greater margin of safety than lignocaine in goat kids. Cornual nerve block (0.5 mL/site) using articaine hydrochloride (1.5%) and lignocaine hydrochloride (1%) alleviated the acute pain during disbudding in goat kids. However, both the drugs provided analgesia only for a short time which necessitates the use of non-steroidal anti-inflammatory drugs (NSAIDs) for postoperative analgesia. In addition, the injection of these drugs at four sites to anaesthetise both the horn buds caused stress and pain in goat kids. Therefore, it is recommended to use sedatives and NSAIDs along with local anaesthetics for disbudding goat kids. However, future studies should evaluate the safety and efficacy of this protocol for disbudding in goat kids. Similar to goat kids, articaine was rapidly hydrolysed to the inactive metabolite, articainic acid, and rapidly eliminated in red deer. A ring block around the base of the antlers using 4% articaine hydrochloride (1 mL/cm pedicle circumference) provided effective analgesia for velvet antler removal in red deer. The results of the studies in red deer suggested that articaine could be a safe and effective local anaesthetic for velvet antler removal. Residue analysis of harvested antlers using liquid chromatography–mass spectrometry (LC–MS) method revealed that the concentrations of articaine and lignocaine in the harvested velvet antlers were similar. Further studies to evaluate the safety of articaine and its metabolites are warranted in target species before recommending articaine hydrochloride as an alternative to lignocaine hydrochloride for velvet antler removal. The analgesic efficacy of methoxyflurane and a novel topical local anaesthetic formulation for disbudding in goat kids were evaluated. Both methoxyflurane and the novel topical formulation provided cutaneous analgesia but did not provide sufficient analgesia for disbudding in goat kids. Further research is required to evaluate the efficacy of these novel analgesic techniques. The efficacy of mepacrine and eugenol for disbudding in goat kids were investigated following subcutaneous injection (0.2 mL) under the horn buds. Both eugenol and mepacrine produced necrosis of horn buds in goat kids but failed to stop horn bud growth. Injection of these compounds using a needle (26 G) and syringe was painful but no pain-related behaviours were seen after the injection. Future studies should evaluate different injection volumes and different non-invasive or minimally invasive administration techniques to increase the efficacy of this novel technique. Refinement of this novel technique might provide a simple, fast, safe and effective way to stop horn bud growth in goat kids.Item Velvet antler removal from red deer : a thesis presented in partial fulfilment of the degree of Doctor of Philosophy in Veterinary Medicine at Massey University, Manawatu, New Zealand(Massey University, 2012) Flint, PaniaAntlers are unique structures specific to deer that are cast and regrown annually. The harvest of velvet antler is a surgical procedure requiring analgesia and haemostasis. Analgesia is provided by lignocaine ring blocks around the base of the antler in adult stags or compression analgesia with a rubber (NaturOTM) ring in yearlings. Stags are often sedated with xylazine for velvet removal. This thesis covers four topics requiring refinement or further understanding: variability in local analgesia using lignocaine; the efficacy or noxiousness of NaturOTM rings; lignocaine residues in antlers; and post- xylazine stag death. In a video observational study of antler harvest on commercial velvet farms, successful analgesia was characterised by fewer “gaps” in the ring block, greater volume of lignocaine per antler, greater time taken to inject lignocaine, greater number of injections, lower stag age, and other stag factors. There was significant confounding in the data and multiple variables are likely to be important. In a series of studies investigating the use of NaturOTM rings, the rings prevented behavioural responses and partially prevented EEG responses to antler removal. On application of the NaturOTM ring, some animals demonstrated behavioural and EEG responses indicative of noxious sensation. NaturOTM rings provide analgesia during antler removal and may cause discomfort on application. It is believed that lignocaine reaches the antler via the blood stream, resulting in tissue residues. Blood flow to the antler was investigated using acrylic models, fluorescent microspheres and cineangiography. Different tourniquet types were tested to determine whether they could prevent lignocaine residues. The arterial supply to the antler is elaborate and tourniquets minimised arterial flow at tensions less than 2kg but did not prevent lignocaine residues. Occasionally, stags die within 48 hours of sedation with xylazine. In an epizoological survey, this was not related to drug or environmental factors. Reactions involved either acute respiratory distress or delayed death with severe pulmonary oedema. During observations of yearlings sedated with xylazine most demonstrated hypoxaemia that could be reversed by oxygen supplementation or yohimbine administration. This work provides indicators of how best practice in velvet antler removal may be improved.Item Prevention of antler growth in deer : a thesis presented in partial fulfilment of the requirements for the degree of Master in Veterinary Clinical Science at Massey University(Massey University, 1996) Weilburg, VeraThe behavioural measures of 31 red and 39 fallow deer yearlings prior to, during and following application of rubber ring to prevent antler growth were determined. Animals were mechanically or manually restrained and treated according to their random allocation to one of the following groups: control (C), local anaesthesia only(LC), local anaesthesia and rubber ring application (LR) , rubber ring application only(R). In a further field trial 45 yearling red deer stags and 84 yearling fallow bucks were randomly allocated to control or rubber ring application. In both studies the development of the pedicle/antler post treatment was examined at intervals to investigate the percentage of loss of pedicle/antler due to the treatment and to detect possible side effects of the treatment. In red deer during the first three hours post treatment a significant increase in walking, standing and feeding and a decrease in lying were seen in the R group. Twenty minutes after treatment the R group showed a significantly higher frequency of scratching. In fallow deer a significant increase in frequency of ear flicks was observed in the R group until six hours post treatment. Other activities (walking,standing, lying) varied significantly at some time periods but no consistent patterns were observed. In both species a substantial reduction of the pedicle/antler could be observed two to four weeks after application of rubber rings. However, the loss of distal parts of the pedicle/antler varied in percentage and time until the loss. A rate of 38-100% regrowth occurred in the first study in fallow and red deer, respectively. In red deer the application of rubber rings stopped further antler growth in 36 of 37 stags thirty days after treatment. The loss of pedicle/antler occurred in 60-66.7%. In fallow deer 93% pedicle/antler loss occurred in bucks. A rate of 10 % regrowth occurred. No infections or other untoward side effects of the treatment were seen.