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| 2. |
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| 3. |
- 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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| 6. |
- 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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| 7. |
- Gabrielsson, Johan, et al.
(författare)
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Animal Health Modeling & Simulation Society: a new society promoting model-based approaches in veterinary pharmacology
- 2013
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Ingår i: Journal of Veterinary Pharmacology and Therapeutics. - : Wiley. - 0140-7783 .- 1365-2885. ; 36, s. 417-419
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The Animal Health Modeling & Simulation Society (AHM&S) is a newly founded association (2012) that aims to promote the development, application, and dissemination of modeling and simulation techniques in the field of Veterinary Pharmacology and Toxicology. The association is co-chaired by Pr. Johan Gabrielsson (Europe), Pr. Jim Riviere (USA), and secretary Dr. Jonathan Mochel (Switzerland). This short communication aims at presenting the membership, rationale and objectives of this group.
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| 8. |
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| 9. |
- Gabrielsson, Johan
(författare)
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Mathematical modeling and simulation in animal Health. Part I: Moving beyond pharmacokinetics
- 2016
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Ingår i: Journal of Veterinary Pharmacology and Therapeutics. - : Wiley. - 0140-7783 .- 1365-2885. ; 39, s. 213-223
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Tidskriftsartikel (refereegranskat)abstract
- The application of mathematical modeling to problems in animal health has a rich history in the form of pharmacokinetic modeling applied to problems in veterinary medicine. Advances in modeling and simulation beyond pharmacokinetics have the potential to streamline and speed-up drug research and development programs. To foster these goals, a series of manuscripts will be published with the following goals: (i) expand the application of modeling and simulation to issues in veterinary pharmacology; (ii) bridge the gap between the level of modeling and simulation practiced in human and veterinary pharmacology; (iii) explore how modeling and simulation concepts can be used to improve our understanding of common issues not readily addressed in human pharmacology (e.g. breed differences, tissue residue depletion, vast weight ranges among adults within a single species, interspecies differences, small animal species research where data collection is limited to sparse sampling, availability of different sampling matrices); and (iv) describe how quantitative pharmacology approaches could help understanding key pharmacokinetic and pharmacodynamic characteristics of a drug candidate, with the goal of providing explicit, reproducible, and predictive evidence for optimizing drug development plans, enabling critical decision making, and eventually bringing safe and effective medicines to patients. This study introduces these concepts and introduces new approaches to modeling and simulation as well as clearly articulate basic assumptions and good practices. The driving force behind these activities is to create predictive models that are based on solid physiological and pharmacological principles as well as adhering to the limitations that are fundamental to applying mathematical and statistical models to biological systems.
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| 11. |
- Held, Felix, et al.
(författare)
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Investigation of sparse clinical sampling in light of baseline oscillations and between‐individual variability using pharmacokinetic/pharmacodynamic modelling
- 2018
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Ingår i: Journal of Veterinary Pharmacology and Therapeutics. Special Issue 14th International Congress of the European Association for Veterinary Pharmacology and Toxicology, Wroclaw, Poland, June 24‐27, 2018, pp146-148. - : Wiley. - 1365-2885.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Cortisol exhibits a circadian rhythm in horses. It is a well‐known biomarker that is suppressed by dexamethasone. A sampling protocol of cortisol with one pre‐ and one post drug administration sample is used in dexamethasone suppression tests. However, diurnal fluctuation and inter‐individual variation may hamper the utility of test results. The aim of this study was to quantify the determinants of baseline fluctuation and between‐individual and between‐occasion variability for guidance of an improved test protocol.
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| 12. |
- Ingvast-Larsson, C., et al.
(författare)
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Clinical pharmacology of buprenorphine in healthy, lactating goats
- 2007
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Ingår i: Journal of Veterinary Pharmacology and Therapeutics. - : Wiley. - 0140-7783 .- 1365-2885. ; 30:3, s. 249-256
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Tidskriftsartikel (refereegranskat)abstract
- The pharmacokinetics and the effects of the opioid buprenorphine on behavior, cardiovascular parameters, plasma concentrations of cortisol and vasopressin were studied in the goat. After intravenous injection at a dosage of 0.02 mg/kg bw, the terminal half-life was 73.8 ± 19.9 min (mean ± SD), the apparent volume of distribution 5.22 ± 1.01 L/kg, and total body clearance 79.1 ± 18.5 mL/min/kg. After intramuscular administration of buprenorphine at the same dosage, bioavailability was complete and clearance was 54.7 ± 16.6 mL/min/kg. Heart rate, blood pressure and concentrations of cortisol and vasopressin in plasma increased after drug administration. The goats became agitated and stopped ruminating. The effects were more pronounced the first time the animals received the drug, especially the influence on the hormone levels. The concentrations of cortisol and vasopressin in plasma remained unaffected after the second dose despite a wash-out period of 3–6 weeks. Buprenorphine may be an unsuitable drug in goats because of the profound inhibition of rumination and the agitation it causes. The short half-life of buprenorphine may limit its use if long-term analgesia is required but be advantageous if a short acting drug is desirable.
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| 13. |
- 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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| 14. |
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| 15. |
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| 16. |
- Mochel, J. P., et al.
(författare)
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Network on veterinary medicines initiated by the European Federation For Pharmaceutical Sciences
- 2018
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Ingår i: Journal of Veterinary Pharmacology and Therapeutics. - : WILEY. - 0140-7783 .- 1365-2885. ; 41:3, s. 378-383
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Tidskriftsartikel (refereegranskat)abstract
- The European Federation for Pharmaceutical Sciences (EUFEPS) was founded 25 years ago by more than 20 national pharmaceutical societies and faculty members. As a pan-European organization, it brings together pharmaceutical societies as well as academic, industrial and regulatory scientists engaged in drug research and development, drug regulation and education of professionals working in these fields. EUFEPS represents pharmaceutical sciences in Europe and is recognized as such by both the European Commission and the European Medicines Agency. EUFEPS cooperates with the European Federation of Pharmaceutical Industries and other European organizations and maintains global connections with agencies such as the US Food and Drug Administration and the American Association of Pharmaceutical Scientists. EUFEPS has established specified networks forming the basis of its activities. The creation of a Network on Veterinary Medicines is prompted by the manifold problems resulting from the use of veterinary drugs and its inherent interconnections with human medicine, environmental and public health. A long-term goal of this initiative was to expand the spectrum of available therapeutics for use in animals, including the development of innovative delivery systems.
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| 17. |
- Olsén, L., et al.
(författare)
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Cetirizine in horses : pharmacokinetics and effect of ivermectin pretreatment
- 2007
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Ingår i: Journal of Veterinary Pharmacology and Therapeutics. - : Wiley. - 0140-7783 .- 1365-2885. ; 30:3, s. 194-200
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Tidskriftsartikel (refereegranskat)abstract
- The pharmacokinetics of the histamine H1-antagonist cetirizine and the effects of pretreatment with the antiparasitic macrocyclic lactone ivermectin on the pharmacokinetics of cetirizine were studied in horses. After oral administration of cetirizine at 0.2 mg/kg bw, the mean terminal half-life was 3.4 h (range 2.9–3.7 h) and the maximal plasma concentration 132 ng/mL (101–196 ng/mL). The time to reach maximal plasma concentration was 0.7 h (0.5–0.8 h). Ivermectin (0.2 mg/kg bw) given orally 1.5 h before cetirizine did not affect its pharmacokinetics. However, ivermectin pretreatment 12 h before cetirizine increased the area under the plasma concentration–time curve by 60%. The maximal plasma concentration, terminal half-life and mean residence time also increased significantly following the 12 h pretreatment. Ivermectin is an inhibitor of P-glycoprotein, which is a major drug efflux transporter in cellular membranes at various sites. The elevated plasma levels of cetirizine following the pretreatment with ivermectin may mainly be due to decreased renal secretion, related to inhibition of the P-glycoprotein in the proximal tubular cells of the kidney. The pharmacokinetic properties of cetirizine have characteristics which are suitable for an antihistamine, and this substance may be a useful drug in horses.
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| 22. |
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| 23. |
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| 24. |
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| 25. |
- Rhodin, Marie, et al.
(författare)
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In vivo joint synovial fluid disposition of a novel sustained-release formulation of diclofenac and hyaluronic acid in horses
- 2022
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Ingår i: Journal of Veterinary Pharmacology and Therapeutics. - : Wiley. - 0140-7783 .- 1365-2885. ; 45, s. 167-176
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Tidskriftsartikel (refereegranskat)abstract
- Intra-articular administration of sustained-release anti-inflammatory drugs is indicated in horses suffering from joint inflammation, but no such drugs are labelled for veterinary use. To obtain initial data on synovial disposition and safety of a new sustained-release formulation of diclofenac (SYN321) in the joints of horses, an experimental interventional study of elimination and side effects of intra-articular administration of SYN321 was conducted. Nine clinically sound horses were included in the study, and SYN321 was administered by the intra-articular route. Dose ranges and sampling intervals were established in a pilot study with two horses, and then applied in a main study involving seven horses treated in the fetlock joint. Diclofenac was detected above lower limit of quantification (LOQ: 0.5 ng/ml) in synovial fluid throughout the study period (14 days), and below LOQ (0.1 ng/ml) in plasma after 4 days and in urine after 14 days. No obvious clinical side effects were detected. Clinical examination and objective lameness evaluation suggested that SYN321 has potential as a local joint NSAID treatment with sustained release in horses, but further studies on synovial fluid exposure, safety and clinical efficacy are warranted.
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| 26. |
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| 29. |
- Tyden, Eva, et al.
(författare)
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Differential gene expression of CYP3A isoforms in equine liver and intestines
- 2012
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Ingår i: Journal of Veterinary Pharmacology and Therapeutics. - : Wiley. - 0140-7783 .- 1365-2885. ; 35, s. 588-595
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Tidskriftsartikel (refereegranskat)abstract
- Tyden, E., Lofgren, M., Pegolo, S., Capolongo, F., Tjalve, H., Larsson, P. Differential gene expression of CYP3A isoforms in equine liver and intestines. J. vet. Pharmacol. Therap. 35, 588595. Recently, seven CYP3A isoforms CYP3A89, CYP3A93, CYP3A94, CYP3A95, CYP3A96, CYP3A97 and CYP129 have been isolated from the horse genome. In this study, we have examined the hepatic and intestinal gene expression of these CYP3A isoforms using TaqMan probes. We have also studied the enzyme activity using luciferin-isopropyl acetal (LIPA) as a substrate. The results show a differential gene expression of the CYP3A isoforms in the liver and intestines in horses. In the liver, CYP3A89, CYP3A94, CYP3A96 and CYP3A97 were highly expressed, while in the intestine there were only two dominating isoforms, CYP3A93 and CYP3A96. The isoform CYP3A129 was not detected in the liver or the intestine, although this gene consists of a complete set of exons and should therefore code for a functional protein. It is possible that this gene is expressed in tissues other than the liver and intestines. In the intestine, both CYP3A96 and CYP3A93 showed the highest gene expression in the duodenum and the proximal parts of the jejunum. This correlated with a high protein expression in these tissues. Studies of the enzyme activity showed the same Km for the LIPA substrate in the liver and the intestine, while the maximum velocity (Vmax) in the liver was higher than in the intestine. Our finding of a differential gene expression of the CYP3A isoforms in the liver and the intestines contributes to a better understanding of drug metabolism in horses.
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| 30. |
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| 31. |
- Tyden, Eva, et al.
(författare)
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Expression and localization of BCRP, MRP1 and MRP2 in intestines, liver and kidney in horse
- 2010
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Ingår i: Journal of Veterinary Pharmacology and Therapeutics. - : Wiley. - 0140-7783 .- 1365-2885. ; 33, s. 332-340
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Tidskriftsartikel (refereegranskat)abstract
- The gene and protein expression and the cellular localization of the ABC transport proteins breast cancer resistance protein (BCRP), multidrug resistance-associated protein 1 (MRP1) and multidrug resistance-associated protein 2 (MRP2) have been examined in the intestines, liver and kidney in horse. High gene and protein expression of BCRP and MRP2 were found in the small intestines, with cellular localization in the apical membranes of the enterocytes. In the liver, MRP2 was present in the bile canalicular membranes of the hepatocytes, whereas BCRP was localized in the cytoplasm of hepatocytes in the peripheral parts of the liver lobuli. In the kidney both BCRP and MRP2 were predominantly present in the distal tubuli and in the loops of Henle. In most tissues, the gene and protein expression of MRP1 were much lower than for BCRP and MRP2. Immunostaining of MRP1 was detectable only in the intestines and with localization in the cytoplasm of enterocytes in the caecum and colon and in the cells of serous acini of Brunner's glands in the duodenum and the upper jejunum. The latter cells were also stained for BCRP, but not for MRP2. Many drugs used in horse are substrates for one or more of the ABC transport proteins. These transporters may therefore have important functions for oral bioavailability, distribution and excretion of substrate compounds in horse.
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| 32. |
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| 33. |
- Tyden, Eva, et al.
(författare)
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P-glycoprotein in intestines, liver, kidney and lymphocytes in horse
- 2009
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Ingår i: Journal of Veterinary Pharmacology and Therapeutics. - : Wiley. - 0140-7783 .- 1365-2885. ; 32, s. 167-176
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Tidskriftsartikel (refereegranskat)abstract
- P-glycoprotein (P-gp) is an important drug transporter, which is expressed in a variety of cells, such as the intestinal enterocytes, the hepatocytes, the renal tubular cells and the intestinal and peripheral blood lymphocytes. We have studied the localization and the gene and protein expression of P-gp in these cells in horse. In addition we have compared the protein sequence of P-gp in horse with the protein sequences of P-gp in several other species. Real time RT-PCR and Western blot showed gene and protein expression of horse P-gp in all parts of the intestines, but there was no strict correlation between these parameters. Immunohistochemistry showed localization of P-gp in the apical cell membranes of the enterocytes and, in addition, staining was observed in the intestinal intraepithelial and lamina propria lymphocytes. Peripheral blood lymphocytes also stained for P-gp, and gene and protein expression of P-gp were observed in these cells. There was a high gene and protein expression of P-gp in the liver, with P-gp-immunoreactivity in the bile canalicular membranes of the hepatocytes. Gene and protein expression of P-gp were found in the kidney with localization of the protein in different parts of the nephrons. Protein sequence alignment showed that horse P-gp has two amino acid insertions at the N-terminal region of the protein, which are not present in several other species examined. One of these is a 99 amino acid long sequence inserted at amino acid positions 23-121 from the N-terminal. The other is a six amino acid long sequence present at the amino acid positions 140-145 from the N-terminal. The results of the present study indicate that P-gp has an important function for oral bioavailability, distribution and excretion of substrate compounds in horse.
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| 34. |
- Tyden, Eva, et al.
(författare)
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The genes of all seven CYP3A isoenzymes identified in the equine genome are expressed in the airways of horses
- 2013
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Ingår i: Journal of Veterinary Pharmacology and Therapeutics. - : Wiley. - 0140-7783 .- 1365-2885. ; 36, s. 370-375
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Tidskriftsartikel (refereegranskat)abstract
- In the present study, we examined the gene expression of cytochrome P450 3A (CYP3A) isoenzymes in the tracheal and bronchial mucosa and in the lung of equines using TaqMan probes. The results show that all seven CYP3A isoforms identified in the equine genome, that is, CYP3A89, CYP3A93, CYP3A94, CYP3A95, CYP3A96, CYP3A97 and CYP3A129, are expressed in the airways of the investigated horses. Though in previous studies, CYP3A129 was found to be absent in equine intestinal mucosa and liver, this CYP3A isoform is expressed in the airways of horses. The gene expression of the CYP3A isoenzymes varied considerably between the individual horses studied. However, in most of the horses CYP3A89, CYP3A93, CYP3A96, CYP3A97 and CYP3A129 were expressed to a high extent, while CYP3A94 and CYP3A95 were expressed to a low extent in the different parts of the airways. The CYP3A isoenzymes present in the airways may play a role in the metabolic degradation of inhaled xenobiotics. In some instances, the metabolism may, however, result in bioactivation of the xenobiotics and subsequent tissue injury.
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| 35. |
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| 36. |
- Wambugu, S. N., et al.
(författare)
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Effects of opioids in the formalin test in the Speke's hinged tortoise (Kinixy's spekii)
- 2010
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Ingår i: Journal of Veterinary Pharmacology and Therapeutics. - : Wiley. - 0140-7783 .- 1365-2885. ; 33:4, s. 347-351
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Tidskriftsartikel (refereegranskat)abstract
- Little is known about analgesia in lower vertebrates such as the Speke's hinged tortoise (Kinixy's spekii), yet of late they are increasingly being adopted as pets. The effects of morphine (5, 7.5, 10 and 20 mg/kg), pethidine (10, 20, and 50 mg/kg) and naloxone (5 mg/kg) on nociception induced by the formalin test (12.5%, 100 mu L) were studied in the Speke's hinged tortoise. Formalin induced a monophasic limb retraction behavioural response and its duration was recorded. The behaviour lasted for 16.4 +/- 0.8 min. Morphine (7.5, 10 and 20 mg/kg) and pethidine (20 and 50 mg/kg) induced significant decrease in the duration of limb retraction in the formalin test. The anti-nociceptive effects were naloxone (5 mg/kg) reversible. The data suggest that the formalin test is a good test for studying nociception and anti-nociception in tortoises and that the opioidergic system plays a role in the control of nociception in these animals.
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