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| 4. |
- Ekstrand, Carl, et al.
(författare)
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A quantitative approach to analysing cortisol response in the horse
- 2016
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Ingår i: Journal of Veterinary Pharmacology and Therapeutics. - : Wiley. - 0140-7783 .- 1365-2885. ; 39:3, s. 255-263
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Tidskriftsartikel (refereegranskat)abstract
- The cortisol response to glucocorticoid intervention has, in spite of several studies in horses, not been fully characterized with regard to the determinants of onset, intensity and duration of response. Therefore, dexamethasone and cortisol response data were collected in a study applying a constant rate infusion regimen of dexamethasone (0.17, 1.7 and 17g/kg) to six Standardbreds. Plasma was analysed for dexamethasone and cortisol concentrations using UHPLC-MS/MS. Dexamethasone displayed linear kinetics within the concentration range studied. A turnover model of oscillatory behaviour accurately mimicked cortisol data. The mean baseline concentration range was 34-57g/L, the fractional turnover rate 0.47-1.5 1/h, the amplitude parameter 6.8-24g/L, the maximum inhibitory capacity 0.77-0.97, the drug potency 6-65ng/L and the sigmoidicity factor 0.7-30. This analysis provided a better understanding of the time course of the cortisol response in horses. This includes baseline variability within and between horses and determinants of the equilibrium concentration-response relationship. The analysis also challenged a protocol for a dexamethasone suppression test design and indicated future improvement to increase the predictability of the test.
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| 9. |
- Ekstrand, Carl, et al.
(författare)
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Cetirizine per os : exposure and antihistamine effect in the dog
- 2018
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Ingår i: Acta Veterinaria Scandinavica. - : BMC. - 0044-605X .- 1751-0147. ; 60
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundCetirizine is an antihistamine used in dogs, but plasma concentrations in relation to effect after oral administration are not well studied. This study investigated cetirizine exposure and the plasma cetirizine concentration-antihistamine response relation in the dog following oral administration of cetirizine.ResultsEight Beagle dogs were included in a cross-over study consisting of two treatments. In treatment one, cetirizine 2-4mg/kg was administered per os once daily for 3days. The other treatment served as a control. Wheal diameter induced by intra-dermal histamine injections served as response-biomarker. Cetirizine plasma concentration was quantified by UHPLC-MS/MS. Median (range) cetirizine plasma terminal half-life was 10h (7.9-16.5). Cetirizine significantly inhibited wheal formation compared with the premedication baseline. Maximum inhibition of wheal formation after treatment with cetirizine per os was 100% compared with premedication wheal diameter. The median (range) IC50-value for reduction in wheal area was 0.33 mu g/mL (0.07-0.45). The median (range) value for the sigmoidicity factor was 1.8 (0.8-3.5). A behavioral study was also conducted and revealed no adverse effects, such as sedation.ConclusionThe results indicate that a once-daily dosing regimen of 2-4mg/kg cetirizine per os clearly provides a sufficient antihistamine effect. Based on this experimental protocol, cetirizine may be an option to treat histamine-mediated inflammation in the dog based on this experimental protocol but additional clinical studies are required.
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| 11. |
- Ekstrand, Carl, et al.
(författare)
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Disposition and effect of intra-articularly administered dexamethasone on lipopolysaccharide induced equine synovitis
- 2019
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Ingår i: Acta Veterinaria Scandinavica. - : BMC. - 0044-605X .- 1751-0147. ; 61
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Tidskriftsartikel (refereegranskat)abstract
- Background: Dexamethasone is used for the intra-articular route of administration in management of aseptic arthritis in horses. Despite its widespread use there is very little quantitative data of the disposition and response to dexamethasone. The aim of this study was to investigate and describe the synovial fluid and plasma dexamethasone concentration over time and to explore the relation between synovial fluid concentration and response using clinical endpoints as response biomarkers after IA injection of dexamethasone disodium salt solution in an equine model of synovitis.Results: Inflammation was induced in the radiocarpal joint of six horses by injection of 2ng lipopolysaccharide (LPS). Two hours later either saline or dexamethasone was injected in the same joint in a two treatment cross over design. Each horse was treated once with one of the six doses dexamethasone used (0.01, 0.03, 0.1, 0.3, 1 or 3mg) and once with saline. Dexamethasone was quantified by means of UHPLC-MS/MS. Dexamethasone disposition was characterised by means of a non-linear mixed effects model. Lameness was evaluated both objectively with an inertial sensor based system and subjectively scored using a numerical scale (0-5). Joint circumference, skin temperature over the joint and rectal temperature were also recorded. The LPS-challenge induced lameness in all horses with high inter-individual variability. Dexamethasone significantly decreased lameness compared with saline. Other variables were not statistically significant different between treatments. Objective lameness scoring was the most sensitive method used in this study to evaluate the lameness response. A pharmacokinetic/pharmacodynamic model was successfully fitted to experimental dexamethasone and lameness data. The model allowed characterization of the dexamethasone synovial fluid concentration-time course, the systemic exposure to dexamethasone after intra-articular administration and the concentration-response relation in an experimental model of synovitis.Conclusions: The quantitative data improve the understanding of the pharmacology of dexamethasone and might serve as input for future experiments and possibly contribute to maintain integrity of equine sports.
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| 12. |
- Ekstrand, Carl, et al.
(författare)
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Plasma concentration-dependent suppression of endogenous hydrocortisone in the horse after intramuscular administration of dexamethasone-21-isonicotinate
- 2015
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Ingår i: Journal of Veterinary Pharmacology and Therapeutics. - : Wiley. - 0140-7783 .- 1365-2885. ; 38:3, s. 235-242
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Tidskriftsartikel (refereegranskat)abstract
- Detection times and screening limits (SL) are methods used to ensure that the performance of horses in equestrian sports is not altered by drugs. Drug concentration-response relationship and knowledge of concentration-time profiles in both plasma and urine are required. In this study, dexamethasone plasma and urine concentration-time profiles were investigated. Endogenous hydrocortisone plasma concentrations and their relationship to dexamethasone plasma concentrations were also explored. A single dose of dexamethasone-21-isonicotinate suspension (0.03mg/kg) was administered intramuscularly to six horses. Plasma was analysed for dexamethasone and hydrocortisone and urine for dexamethasone, using UPLC-MS/MS. Dexamethasone was quantifiable in plasma for 8.3 +/- 2.9days (LLOQ: 0.025g/L) and in urine for 9.8 +/- 3.1days (LLOQ: 0.15g/L). Maximum observed dexamethasone concentration in plasma was 0.61 +/- 0.12g/L and in urine 4.2 +/- 0.9g/L. Terminal plasma half-life was 38.7 +/- 19h. Hydrocortisone was significantly suppressed for 140h. The plasma half-life of hydrocortisone was 2.7 +/- 1.3h. Dexamethasone potency, efficacy and sigmoidicity factor for hydrocortisone suppression were 0.06 +/- 0.04g/L, 0.95 +/- 0.04 and 6.2 +/- 4.6, respectively. Hydrocortisone suppression relates to the plasma concentration of dexamethasone. Thus, determination of irrelevant plasma concentrations and SL is possible. Future research will determine whether hydrocortisone suppression can be used as a biomarker of the clinical effect of dexamethasone.
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| 14. |
- Gabrielsson, Johan, et al.
(författare)
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Maxsim2-Real-time interactive simulations for computer-assisted teaching of pharmacokinetics and pharmacodynamics.
- 2014
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Ingår i: Computer methods and programs in biomedicine. - : Elsevier BV. - 1872-7565 .- 0169-2607. ; 113, s. 815-829
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Tidskriftsartikel (refereegranskat)abstract
- We developed a computer program for use in undergraduate and graduate courses in pharmacology, pharmacokinetics and pharmacodynamics. This program can also be used in environmental and toxicological studies and preclinical simulation, to facilitate communication between modeling pharmacokineticists and project leaders or other decision-makers in the pharmaceutical industry. The program simulates the drug delivery and transport by means of (I) a six-compartment physiological pharmacokinetic flow model, (II) a system of traditional compartment models, or (III) a target-mediated drug disposition system. The program also can be used to simulate instantaneous equilibria between concentration and pharmacodynamic response, or as temporal delays between concentration and response. The latter is done by means of turnover models (indirect response models). Drug absorption, distribution, and elimination are represented by differential equations, which are described by organ and tissue volumes or other volumes of distribution, blood flows, clearance terms, and tissue-to-blood partition coefficients. The user can control and adjust these parameters by means of a slider in real time. By interactively changing the parameter values and simultaneously displaying the resulting concentration-time and/or response-time profiles, users can understand the major mechanisms that govern the disposition or the pharmacological response of the drug in the organism in real time. Schedule dependence is typically seen in clinical practice with a non-linear concentration-response relationship, and is difficult to communicate except via simulations. Here, we sought to illustrate the potential advantages of this approach in teaching pharmacology, pharmacokinetics, and pharmacodynamics to undergraduate pharmacy-, veterinary-, and medical students or to project teams in drug discovery/development.
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| 15. |
- Ingvast Larsson, Carina, et al.
(författare)
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Clinical pharmacology of methadone in dogs
- 2010
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Ingår i: Veterinary Anaesthesia and Analgesia. - : Elsevier BV. - 1467-2987 .- 1467-2995. ; 37:1, s. 48-56
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate the pharmacokinetics and effects of methadone on behaviour and plasma concentrations of cortisol and vasopressin in healthy dogs. Study design Randomized, cross-over, experimental trial. Animals Nine adult dogs (beagle and beagle cross breeds), four males and five females. Methods Methadone hydrochloride, 0.4 mg kg-1, was administered intravenously (IV) and subcutaneously (SC) with a crossover design. Drug and hormone analyses in plasma were performed using Liquid Chromatography-Electrospray Ionization-Tandem Mass Spectrometry and radioimmunoassay respectively. Behavioural data were collected using a standardized protocol. Results After IV administration, the plasma concentration of methadone at 10 minutes was 82.1 +/- 9.2 ng mL-1 (mean +/- SD), the terminal half-life was 3.9 +/- 1.0 hours, the volume of distribution 9.2 +/- 3.3 L kg-1 and plasma clearance 27.9 +/- 7.6 mL minute-1 kg-1. After SC administration, time to maximal plasma concentration was 1.26 +/- 1.04 hours and maximal plasma concentration of methadone was 23.9 +/- 14.4 ng mL-1, the terminal half-life was 10.7 +/- 4.3 hours and bioavailability was 79 +/- 22%. Concentrations of both cortisol and vasopressin were increased for an hour following IV methadone. The observed behavioural effects of methadone were decreased licking and swallowing and an increase in whining after SC administration. The latter finding is notable as it can be misinterpreted as pain when methadone is used as an analgesic. Conclusion and clinical relevance When methadone was administered by the SC route, the half-life was longer, but the individual variation in plasma concentrations was greater compared with IV administration. Increased frequency of whining occurred after administration of methadone and may be a drug effect and not a sign of pain. Cortisol and vasopressin concentrations in plasma may not be suitable for evaluating analgesia after methadone treatment.
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| 17. |
- Ingvast Larsson, Carina, et al.
(författare)
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Pharmacokinetics of meloxicam in adult goats and its analgesic effect in disbudded kids
- 2011
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Ingår i: Journal of Veterinary Pharmacology and Therapeutics. - : Wiley. - 0140-7783 .- 1365-2885. ; 34:1, s. 64-69
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Tidskriftsartikel (refereegranskat)abstract
- The pharmacokinetics and analgesic effect of the nonsteroidal anti-inflammatory drug meloxicam (0.5 mg/kg) in goats were investigated. In a randomized, cross-over design the pharmacokinetic parameters were investigated in adult goats (n = 8) after single intravenous and oral administration. The analgesic effect was evaluated in kids using a randomized, placebo controlled and blinded protocol. Kids received meloxicam (n = 6) once daily and their siblings (n = 5) got isotonic NaCl intramuscularly while still anaesthetized after cautery disbudding and injections were repeated on three consecutive days. In the adult goats after intravenous administration the terminal half-life was 10.9 ± 1.7 h, steady-state volume of distribution was 0.245 ± 0.06 L/kg, and total body clearance was 17.9 ± 4.3 mL/h/kg. After oral administration bioavailability was 79 ± 19%, C(max) was 736 ± 184 ng/mL, T(max) was 15 ±5 h, although the terminal half-life was similar to the intravenous value, 11.8 ± 1.7 h. Signs of pain using a visual analogue scale were smaller in kids treated with meloxicam compared with kids treated with placebo on the first day after disbudding, but subsequently no difference in pain was noticeable. Plasma cortisol and glucose concentrations did not differ between the two groups.
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| 19. |
- Olsén, Lena, et al.
(författare)
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Behaviour and respiratory rate after administration of methadone and methadone in combination with detomidine in horses
- 2016
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Ingår i: Acta Veterinaria Scandinavica. - : Springer Science and Business Media LLC. - 1751-0147.
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Konferensbidrag (refereegranskat)abstract
- Background: In treatment of nociceptive pain with opioids the full μ-agonists have highest efficacy. Methadone is a synthetic full μ-agonist and also an N-methyl-d-aspartate (NMDA) receptor antagonist used in horses. Opioids might also cause excitement in the horse and respiratory depression especially when used together with other drugs affecting the respiration. The α2-agonists are used in horses for sedation and analgesia both separately and in combination with opioids. A combination of methadone and the α2-agonist detomidine may be useful in pain management but may also cause effects on behaviour and respiratory rate. Objectives: The aims were to investigate the effects on behavior and respiratory rate after treatment with methadone IV or methadone IV in combination with detomidine IM in order to evaluate and possibly diminish adverse effects in the treatment of horses. Materials and methods: The study was randomized, blinded and placebo controlled with cross-over design. Eight Standardbred horses were treated with (1) methadone IV (0.2 mg/kg) in a total volume of 20 mL over 5 min together with placebo (saline) IM or (2) 20 mL methadone IV (0.1 mg/kg) over 5 min together with detomidine IM (0.01 mg/kg) or (3) equivalent volumes saline IV and IM. The effects on behavior and respiratory rate were examined. Results: After methadone administration the horses displayed behavioral changes such as staggering for a short period, head tremors and looking vigilantly around. The behaviors licking, nodding head, picking hay, tail flapping, skin twitching and scraping with front leg were more frequent after treatment with methadone compared to the control. There were no differences in respiratory rate between methadone and saline treatments. After methadone/detomidine administration the horses showed drowsiness, snored, stood with dropped head or head supported by the wall or the crib during the first one to three hours. In addition, a few horses were sweating. The respiratory rate was lowered between one and three hours after administration of the drug combination compared with placebo (P = 0.02). Conclusions: When the horses were treated with methadone they showed drug-related agitation which has been described in horses treated with different opioids. The combination of methadone/detomidine seems to prevent excitement caused by opioid exposure. A lowered respiratory rate is also a known non-wanted effect of opioids but in this study no such adverse effect was observed after solely methadone administration but the combination methadone/detomidine induced decreased respiratory rate. Acknowledgements: Supported by The Swedish-Norwegian Foundation for Equine Research.
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| 20. |
- Olsén, Lena, et al.
(författare)
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Cetirizine in horses : Pharmacokinetics and pharmacodynamics following repeated oral administration
- 2008
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Ingår i: The Veterinary Journal. - : Elsevier BV. - 1090-0233 .- 1532-2971. ; 177:2, s. 242-249
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Tidskriftsartikel (refereegranskat)abstract
- The pharmacokinetics of the histamine HI-antagonist cetirizine and its effect on histamine-induced cutaneous wheal formation were studied in six healthy horses following repeated oral administration. After three consecutive administrations of cetirizine (0.2 mg/kg body weight, bw) every 12 h, the trough plasma concentration of cetirizine was 16 +/- 4 ng/mL (mean +/- SD) and the wheal formation was inhibited by 45 +/- 23%. After four additional administrations of cetirizine (0.4 mg/kg bw) every 12 h, the trough plasma concentration was 48 +/- 15 ng/mL and the wheal formation was inhibited by 68 +/- 11%. The terminal half-life was about 5.8 h. A pharmacokinetic/ pharmacodynamic link model showed that the maximal inhibition of wheal formation was about 95% and the EC50 about 18 ng/mL. It is concluded that cetirizine in doses of 0.2-0.4 mg/kg bw administered at 12 h intervals exhibits favourable pharmacokinetic and pharmacodynamic properties without causing visible side effects, and the drug may therefore be a useful antihistamine in equine medicine.
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| 22. |
- Olsén, Lena, et al.
(författare)
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Intramuscular administration of sodium benzylpenicillin in horses as an alternative to procaine benzylpenicillin
- 2013
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Ingår i: Research in Veterinary Science. - : Elsevier BV. - 0034-5288 .- 1532-2661. ; 95:1, s. 212-218
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Tidskriftsartikel (refereegranskat)abstract
- The aim was to supply information about the possibility of replacing the procaine salt with the sodium salt for benzylpenicillin IM treatment in horse in order to diminish the risk for procaine adverse effects. In a crossover study eight horses were given 15 mg/kg sodium benzylpenicillin (Na-pc) twice daily or procaine benzylpenicillin (control) once daily IM for four days. The half-life of Na-pc was 1.9 h, peak concentration was 14,600 ng/mL reached after about 23 min. Trough plasma concentration Was 281 ng/mL and protein binding 62.8%. The fT > MIC for Staphylococcus aureus was 63% and 100% for Streptococcus equi subsp. equi and Streptococcus zooepidemicus, indicating an adequate antimicrobial therapy. However, Na-pc cannot be recommended from a welfare point of view since the horses showed more pain related behaviour and more pain and swelling compared to the control treatment.
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| 23. |
- Olsén, Lena, et al.
(författare)
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Methadone in healthy goats : Pharmacokinetics, behaviour and blood pressure
- 2013
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Ingår i: Research in Veterinary Science. - : Elsevier BV. - 0034-5288 .- 1532-2661. ; 95:1, s. 231-237
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Tidskriftsartikel (refereegranskat)abstract
- The pharmacokinetics and effects of the opioid methadone on behaviour, arterial blood pressure, heart rate and haematocrit were studied in goats. Two goats received methadone (0.2 mg/kg) intravenously and the terminal half-life was 88 and 91 min, the volume of distribution 8.4 and 6.1 L/kg, and clearance 86 and 123 mL/min/kg. In a crossover study eight goats received methadone (0.6 mg/kg) or 0.15 M NaCl subcutaneously (SC). After SC administration bioavailability was complete and the terminal half-life was 215 +/- 84 min (mean +/- SD), T-max 31 +/- 15 min and C-max 45 +/- 11 ng/mL. Blood pressure and haematocrit increased while heart rate did not change. The goats did not ruminate and they climbed, scratched, gnawed and showed tail-flicking after SC methadone in contrast to NaCl administration. The use of methadone in goats may be restricted due to the inhibition of rumination and the rather short half-life.
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| 25. |
- Olsén, Lena, et al.
(författare)
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Optimizing thermal testing system in the horse
- 2016
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Ingår i: Acta Veterinaria Scandinavica. - 0044-605X .- 1751-0147. ; 58
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background: Accurate, repeatable and reliable pain recognition and quantification of analgesia are essential for development of effective analgesic protocols and necessary for adequate pain management. Thermal threshold testing techniques have valuable roles in both the identification of altered nociceptive function and the pre-clinical evaluation of analgesics in horses. When using test systems, definition of a clear cut end-point of stimulation, such as skin twitching, shaking or hoof withdrawal is crucial for reliable and repeatable determination of the nociceptive threshold. End-point behaviour might be reflex related or may represent conscious perception of pain but could also be influenced by the environment and the horse's willingness to show pain. Objectives: The overall aim was to optimise the reliability and repeatability of the testing procedures in a future study assessing analgesic treatment protocols. The optimal settings of the testing system was evaluated. Furthermore, the type of end-point behavior showed by different horses was investigated. Materials and methods: Fifteen Standardbred horses were evaluated using a thermal threshold testing system adopted for use in horses (Topcat Metrology). All horses were tested by heating with a thermal probe on skin at the withers until an end-point behaviour (threshold temperature) or a cut-out temperature (58 °C) was reached. The type of end-point behaviour, the willingness to wear the testing system and to show pain related behaviour was evaluated. Also the skin temperature before heating, the rate of heating (0.5 vs 1.0 °C/s) and repeatability was examined. The study was blinded with cross-over design. Results: No differences in mean threshold temperature (49.5 and 50.7 °C, respectively) between the rates of heating of 0.5 vs 1.0 °C/s, nor in delta temperature (14.0 and 14.4 °C, respectively). There were individual differences in type of behaviour and easiness to observe their end-point behaviour and some horses did not produce an identifiable end-point behaviour before cut-out temperature. We identified and selected horses showing easy recognized skin twitch as end-point behavior to be included in our future study of analgesic treatments. Conclusions: Thermal threshold testing appears not to be an appropriate test technique in all individual horses. As higher cut-out temperatures could possibly damage the skin it is not appropriate to include more "stoic" horses. This implies that if pain is more easily identified in extrovert individuals the relationships between pain behavior and personality in horses should be clarified for better study design in pain management. Acknowledgements: Supported by The Swedish-Norwegian Foundation for Equine Research.
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