The pharmacodynamics of zuclopenthixol acetate in horses
Abstract: 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.
AT THIS PAGE YOU CAN DOWNLOAD THE WHOLE ESSAY. (follow the link to the next page)