The pharmacodynamics of zuclopenthixol acetate in horses
Stress is an important homeostatic function which may not always be entirely positive for the individual. It has been found that stress both has the ability to amplify and reduce pain. Also, pain may induce stress and fear. An important element of pain assessment in horses is the observation of c...
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| Formato: | Second cycle, A2E |
| Lenguaje: | sueco Inglés |
| Publicado: |
2016
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| Acceso en línea: | https://stud.epsilon.slu.se/9904/ |
| Sumario: | Stress is an important homeostatic function which may not always be entirely positive for the
individual. It has been found that stress both has the ability to amplify and reduce pain. Also,
pain may induce stress and fear. An important element of pain assessment in horses is the
observation of certain pain-induced changes in the horses’ behaviour. When pain is
accompanied with stress and fear, behavioural pain assessments may therefore be flawed.
Long-acting neuroleptics (LANs) have been used empirically to reduce stress during handling
and transportation of wild animals. Zuclopenthixol acetate (ZUP) is a LAN that has shown
valuable properties within this area. Acepromazine, a neuroleptic commonly used in horses
today, has a pronounced sedative effect which is not desirable for long term treatment or for
observations of behaviour. It would therefore be advantageous if ZUP had the same fear
reducing effect on horses as in wild animals without sedative acting as acepromazine. Studies
on the basic pharmacodynamics and pharmacokinetic properties of ZUP have not been
published for other species than man. Doses and treatment regimens used in wildlife species
have thus been established entirely on a trail and error basis. The objective of this study was
to establish a dose of ZUP that would reduce fear or stress in horses, but not induce side
effects by testing certain pharmacodynamic proerties of selected ZUP doses extrapolated from
earlier wildlife studies. Four horses were included in two dose-range finding pilot studies and
four other horses were included in a pharmacodynamic study. In the two dose-range finding
pilot studies the horses were given either 1 mg/kg, 0.5 mg/kg, 0.25 mg/kg or 0.1 mg/kg as a
single intramuscular injection of ZUP (Cisordinol-Acutard® or Clopixol-Acutard®). Based on
the findings in the pilot studies, the dose 0.25 mg/kg was used in a pharmacodynamic
observer blinded, placebo controlled, randomised, cross over designed study. That study was
conducted in two six-day study sessions with an eight days wash out period in between. Fear
behaviour was tested via a Novel Object Test (NOT), sedation and ataxia was scored using
two descriptive scales. These experiments were repeated in each study session. Blood
sampling was performed for the pharmacokinetic profile presented in the thesis of Belfrage
(2016). Two horses scored a higher reactivity score in the NOT when given placebo
compared to ZUP. One of theese horses also had a slightly elevated sedation score on Day 1
and 3 and showed signs of mild ataxia on Day 3. None of the other horses were scored as
sedated or ataxic at any occasion. Overall, the heartrate elevation was larger in the NOT that
was performed in Day 2 compared to Day 4 each study session (P=0.027) which indicates a
habitual effect to the NOT. The effect of ZUP seems to be highly individual since there were
no noticeable effects in two horses administered 0.25 mg/kg, while a thrid horse had side
effects from that same dose. Side effects that were documented for doses 0.25 mg/kg, 0.5
mg/kg and 1 mg/kg and comprised extrapyramidal symptoms, muscle fasciculations,
inappetence, aggressive behaviour, tachycardia, colic and submandibular edema. The dose 1
mg/kg was chosen because it is recommended for use in several wild life studies including
ruminants. No empiric recommendations exist for equids. However the dose of 0.25 mg/kg
also caused some side effects which indicates that horses may be more sensitive to this
substance than several other species. Since the pharmacodynamic study included only four
horses it is not possible to draw any valid conclusion about the drugs’ potential anxiolytic
effect in horses. The substance may though have an anxiolytic or stress reducing effect in
horses since reduction of fear related behaviour to a quite scary novel object was observed in
two out of four horses administered 0.25 mg/kg. A safe and at the same time effective dose
recommendation of ZUP for horses could therefore not be established in this study. Since
horses have shown high sensitivity to ZUP and the drug has a long acting time, the future use
of ZUP and the formulations of the drug should be thoroughly considered when proceeding
with research. |
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