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...
| Autor principal: | |
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| Formato: | Second cycle, A2E |
| Lenguaje: | sueco Inglés |
| Publicado: |
2016
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| Materias: | |
| Acceso en línea: | https://stud.epsilon.slu.se/9904/ |
| _version_ | 1855571604093796352 |
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| author | Ödmark, Petra |
| author_browse | Ödmark, Petra |
| author_facet | Ödmark, Petra |
| author_sort | Ödmark, Petra |
| collection | Epsilon Archive for Student Projects |
| description | 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. |
| format | Second cycle, A2E |
| id | RepoSLU9904 |
| institution | Swedish University of Agricultural Sciences |
| language | Swedish Inglés |
| publishDate | 2016 |
| publishDateSort | 2016 |
| record_format | eprints |
| spelling | RepoSLU99042017-09-02T23:15:05Z https://stud.epsilon.slu.se/9904/ The pharmacodynamics of zuclopenthixol acetate in horses Ödmark, Petra Miscellaneous animal disorders 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. Stress är en viktig homeostatisk funktion som inte enbart är positiv för individen. Studier har visat att stress både kan amplifiera och reducera smärta. Smärta kan också inducera stress och rädsla. En viktig del av smärtbedömning hos häst är att observera speciella smärtinducerade förändringar i hästarnas beteende, men när smärta åtföljs av stress och rädsla kan dessa beteendebedömningar bli bristfälliga. Långtidsverkande neuroleptikum (LAN) har använts empiriskt för att reducera stress vid hantering och transport av vilda djur. Zuklopentixol acetat (ZUP) är ett LAN som har visats ha värdefulla egenskaper inom detta område. Acepromazin, ett neuroleptikum som ofta används till häst idag, har en uttalad sederande effekt. Denna effekt är dock inte önskvärt vid långtidsbehandling eller vid beteendeobservationer. Det vore därför fördelaktigt om ZUP visade samma anxiolytiska effekt hos häst som hos vilda djur utan att verka sederande som acepromazin. Studier på ZUPs basala farmakodynamiska och farmakokinetiska egenskaper har inte publicerats för andra djurslag än människa. De doser som använts vid hantering av vilda djur har enbart fastställts genom “trial and error”. Målet med denna studie var att fastställa en dos ZUP som reducerar stress och rädsla hos hästar utan att inducera biverkningar genom att testa specifika farmakodynamiska egenskaper hos utvalda ZUP-doser, extrapolerade från tidigare studier med vilda djur. Fyra hästar inkluderades i två pilotstudier för att finna lämplig dos och fyra andra hästar inkluderades i en farmakodynamisk studie. I de två pilotstudierna gavs hästarna antingen 1 mg/kg, 0,5 mg/kg, 0,25 mg/kg eller 0,1 mg/kg som en enkel intramuskulär injektion av ZUP (Cisordinol-Acutard® eller Clopixol-Acutard®). Baserat på resultaten från pilotstudien användes dosen 0,25 mg/kg i en farmakodynamisk observerarblindad, placebokontrollerad, randomiserad, cross over-studie. Studien delades upp i två sexdagarssessioner med åtta dagars “wash out” mellan. Rädslereaktioner utvärderades med hjälp av ett Novel Object Test (NOT), sedering och ataxi bedömdes utifrån två deskriptiva skalor. Dessa experiment upprepades under varje studiesession. Blodprover togs för att få fram en farmakokinetisk profil som presenteras i en uppsats av Belfrage (2016). Två hästar bedömdes ha en högre reaktionsgrad vid NOT då de administrerats placebo jämfort med ZUP. En av dessa hästar bedömdes också milt sederad dag 1 och dag 3 och visade tecken på mild ataxi dag 3. Ingen av de andra hästarna bedömdes vara sederade eller visa tecken på ataxi vid något tillfälle. Hjärtfrekvensstegringen var generellt högre i det NOT som utfördes dag 2 jämfört med dag 4 i båda studiesessionerna (P=0,027), vilket indikerar en habitueringseffekt. Doseringen verkar vara mycket individuell då två hästar inte uppvisade någon effekt av 0,25 mg/kg, medan en annan fick biverkningar av samma dos. Biverkningar dokumenterades vid administrarion av doserna 0,25 mg/kg, 0,5 mg/kg och 1 mg/kg och innefattade extrapyramidala symptom, muskelfascikulationer, inappetens, aggressivitet, takykardi, kolik och submandibulärt ödem. Dosen 1 mg/kg valdes då den rekommenderas i flera studier med vilda djur inklusive idisslare. Inga empiriska rekommendationer finns för hästdjur. Dosen på 0,25 mg/kg gav, som tidigare nämnts, också upphov till biverkningar vilket indikerar att häst är mer känslig mot substansen än flera andra djurslag. Eftersom den farmakodynamiska studien endast inkluderade en population av fyra hästar försvårar det möjligheten att dra några slutsatser kring substansens potentiella anxiolytiska effekt hos häst. Substansen kan dock ha en anxiolytisk eller stressreducerande effekt hos hästar då reduktion av rädslerelaterat beteende mot ett skrämmande föremål observerades hos två av fyra hästar doserade 0,25mg/kg. En säker och samtidigt effektiv dos kunde inte fastställas i den här studien och hästarna har uppvisat hög känslighet för substansen, vilket bör tas i noga beaktning vid eventuellt fortskridande av denna forskning. 2016-12-28 Second cycle, A2E NonPeerReviewed application/pdf sv https://stud.epsilon.slu.se/9904/1/odmark_p_170118.pdf Ödmark, Petra, 2016. The pharmacodynamics of zuclopenthixol acetate in horses. Second cycle, A2E. Uppsala: (VH) > Dept. of Clinical Sciences (until 231231) <https://stud.epsilon.slu.se/view/divisions/OID-715.html> urn:nbn:se:slu:epsilon-s-6161 eng |
| spellingShingle | Miscellaneous animal disorders Ödmark, Petra The pharmacodynamics of zuclopenthixol acetate in horses |
| title | The pharmacodynamics of zuclopenthixol acetate in horses |
| title_full | The pharmacodynamics of zuclopenthixol acetate in horses |
| title_fullStr | The pharmacodynamics of zuclopenthixol acetate in horses |
| title_full_unstemmed | The pharmacodynamics of zuclopenthixol acetate in horses |
| title_short | The pharmacodynamics of zuclopenthixol acetate in horses |
| title_sort | pharmacodynamics of zuclopenthixol acetate in horses |
| topic | Miscellaneous animal disorders |
| url | https://stud.epsilon.slu.se/9904/ https://stud.epsilon.slu.se/9904/ |