Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.788578
Title: Actions of non-steroidal anti-inflammatory drugs in sheep
Author: Welsh, Elizabeth McCaull
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1993
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Abstract:
Mechanical and thermal stimuli were used to determine threshold responses in normal experimental sheep which were familiar with both test procedures. The average control response threshold to noxious thermal and mechanical stimulation was 54.5°C and 3.2 Newtons (N), respectively. The effects of 2 non-steroidal anti-inflammatory drugs (NSAIDs), flunixin meglumine and carprofen, were investigated using the 2 test systems. Neither drug was shown to influence thresholds to noxious stimulation over a 6 hour period in normal sheep. Thresholds to noxious mechanical stimulation were .recorded from normal farm sheep which were unfamiliar with the testing procedure. The average response threshold in these sheep was significantly greater than that recorded from experimental sheep (mean, 4.9N), but fell over a period of 3 days to a similar level recorded from experimental sheep (mean, 3.IN). Thresholds to noxious mechanical stimulation in farm sheep which were unfamiliar with the testing procedure, and which had been suffering from footrot for a period of not less than 1 week, were not significantly different from normal farm sheep (mean, 4.7N). In addition, when these sheep were tested over a period of 3 days, thresholds did not fall in the manner described for normal sheep (mean, 4.6N). However, administration of flunixin meglumine, 1.0 mg/kg, IV, once daily for 3 days in sheep suffering from footrot caused a significant reduction in thresholds to noxious mechanical stimulation in sheep suffering from footrot on the third and fourth days after treatment had been initiated. Thresholds to noxious mechanical and thermal stimulation were assessed in sheep undergoing anaesthesia and abdominal surgery, and the effects of flunixin meglumine, carprofen and buprenorphine, a partial opioid agonist, on thresholds investigated. Induction of anaesthesia was achieved by injection of thiopentone or ketamine, IV, and anaesthesia was maintained by administration of halothane in oxygen and nitrous oxide. After thiopentone induction, thermal and mechanical thresholds were not shown to change after a 20 minute period of general anaesthesia alone, and similarly, thresholds to noxious mechanical stimulation were not significantly different from control values after induction of anaesthesia with either thiopentone or ketamine in sheep which underwent abdominal surgery. However, after thiopentone induction, thresholds to noxious thermal stimulation were significantly lower than control values 45, 60 and 120 minutes postoperatively. Intra-operative injection of flunixin meglumine (1.0 mg/kg, IV) and buprenorphine (10 μg/kg, IV) prevented the development of post-operative thermal hyperalgesia, while carprofen (4.0 mg/kg, IV), not only prevented the development of hyperalgesia in the immediate post-operative period, but also caused a significant increase in thresholds to noxious thermal stimulation 60 minutes post-operatively. Thresholds to noxious thermal stimulation were unchanged in the post-operative period in sheep anaesthetised with ketamine which subsequently had undergone abdominal surgery under halothane anaesthesia. Thresholds to noxious mechanical stimulation were investigated during peripheral limb ischaemia, induced by application of a pneumatic tourniquet to the forelimb of sheep. During limb ischaemia, mechanical thresholds fell to below control values, and immediately prior to tourniquet deflation, were significantly lower than those recorded pre-inflation (3.IN vs 1.7N). Injection of flunixin meglumine (1.0 mg/kg, IV) and carprofen (0.7 mg/kg, IV) 1 hour prior to tourniquet inflation attenuated the fall in mechanical thresholds recorded after injection of saline (5 ml (0.9 %), IV) 1 hour before inflation. Similarly, administration of fentanyl (5 jLig/kg, IV), a fi-opioid agonist, prevented the reduction in thresholds observed during tourniquet inflation. Thresholds to noxious mechanical and thermal stimulation were assessed for a period of 120 minutes after intradermal injection of saline (0.9 %, 100 fil) or the irritant carrageenan (0.0625%, 100 p.1). Flunixin meglumine (2.0 mg/kg, IV), carprofen (4.0 mg/kg, IV) or saline (5 ml (0.9 %), IV) was administered at 120 minutes, and subsequently, thresholds to noxious stimulation were investigated for a further 4 hours. Intradermal injection of carrageenan did not cause a clearly defined change in thresholds to noxious mechanical stimulation, but thresholds to thermal stimulation were significantly lower than control values 120 minutes after injection of the irritant (group mean, 52.4°C vs 49.3°C). Thresholds to noxious thermal stimulation remained significantly lower than control values after administration of saline, IV, for a further 60 minutes. However, after administration of either NSAID, thresholds were no longer significantly different from control values. Pharmacokinetic analyses of plasma levels of flunixin meglumine and carprofen (0.7 and 4.0 mg/kg) following intravenous injection in sheep was carried out. The decline of flunixin meglumine in plasma was best described by a tri-exponential equation, after injection of both 1.0 and 2.0 mg/kg, with elimination half-lives of 221.7 and 205.8 minutes, respectively. The decline of carprofen in plasma was best described by a biexponential equation, after injection of both 0.7 and 4.0 mg/kg, with elimination halflives of 25.8 and 32.3 hours, respectively. A comparison of 2 subjective rating scales, an numerical rating scale (NRS) and a visual analogue scale (VAS), for rating lameness in sheep was made. Both scales were shown to be reproducible and repeatable, but the VAS was more sensitive than the NRS and did not force observers to group unlike data. It was dem onstrated that although reproducibility of both the VAS and NRS was poor when an untrained observer was compared with a trained observer, the repeatability of both scales was good for untrained as well as trained observers. The VAS was used to score a group of sheep for lameness and to assess the response to flunixin meglumine (1.0 or 2.0 mg/kg, IV) over a 6 hour period after injection. No significant differences were shown between the 2 different dose rates used in the study, nor were there any significant differences within either group. However, injection of flunixin meglumine caused a reduction in lameness in >80% of sheep administered the lower dose at some time after injection, while >70 % of sheep administered the higher dose rate showed a similar reduction.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.788578  DOI: Not available
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