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- Olsén, Lena, et al.
(author)
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Cetirizine in horses : Pharmacokinetics and pharmacodynamics following repeated oral administration
- 2008
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In: The Veterinary Journal. - : Elsevier BV. - 1090-0233 .- 1532-2971. ; 177:2, s. 242-249
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Journal article (peer-reviewed)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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- Lindström, Veronica, 1978-
(author)
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Adrenocorticolysis Induced by 3-MeSO2-DDE : Mechanisms of Action, Kinetics and Species Differences
- 2007
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Doctoral thesis (other academic/artistic)abstract
- The DDT metabolite 3-methylsulphonyl-DDE (3-MeSO2-DDE) induces cell death specifically in the adrenal cortex of mice after a cytochrome P45011B1 (CYP11B1)-catalysed bioactivation. This substance is not only an environmental pollutant, but also a suggested lead compound for an improved chemotherapy of adrenocortical carcinoma (ACC). The aim of the thesis was to further investigate this compound in terms of kinetics, cell death mechanisms and species differences. The pharmacokinetics of 3-MeSO2-DDE and the current drug for ACC, o,p’-DDD, was studied during 6 months following a single dose in minipigs. The elimination was slower for 3-MeSO2-DDE than for o,p’-DDD, indicated by a lower clearance and longer t½ in plasma and subcutaneous fat. Both substances remained in fat tissue during the whole study period. Unlike o,p’-DDD, 3-MeSO2-DDE was retained also in liver. The adequacy of the murine adrenocortical cell line Y-1 was evaluated for studies of adrenotoxic compounds. The Y-1 cells proved to be an appropriate test system for future mechanism studies, since CYP-catalysed irreversible binding, inhibited corticosterone production induced by 3-MeSO2-DDE and o,p’-DDD were successfully demonstrated. Cell death of 3-MeSO2-DDE in the mouse adrenal cortex was implied to be necrotic. Early apoptotic signalling (i.e. up-regulation of caspase-9) was observed, although it seemed to be interrupted by ATP-depletion and anti-apoptotic actions by heat shock protein 70, resulting in lack of activation of caspase-3. Using cultured adrenal tissue slices, two not previously studied species were examined ex vivo regarding adrenal binding of 3-MeSO2-[14C]DDE. Binding was found in the hamster adrenal cortex and in assumed cortical cells in the medulla, while the guinea pig adrenal was devoid of binding. This emphasises the species specificity in bioactivation of 3-MeSO2-DDE. The thesis forms a basis for further investigations in the human adrenocortical cell line H295R and provides new knowledge of importance for toxicological risk assessment of 3-MeSO2-DDE.
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| 4. |
- Lundgren, Magnus, 1981-
(author)
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Coxsackievirus B3 Infection and Host Defence Responses Change the Metabolism of PBDE
- 2009
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Doctoral thesis (other academic/artistic)abstract
- It has been suggested that the rising amounts of chemicals in the environment may affect host resistance and increase susceptibility to infections. Studies have also shown that infections can change the toxicity of pollutants. The aim of this thesis was to study interactions between environmental pollutant exposure in terms of polybrominated diphenyl ethers (PBDE) and a common human coxsackievirus B3 (CVB3) infection adapted to Balb/c mice. The studies focused on virus levels, cytokines, metabolising cytochrome P450 (CYP) enzymes and tissue distribution of PBDE. A novel finding was an organ-specific effect of CVB3 infection on the metabolising capacity of PBDE. The PBDE metabolising enzyme CYP2B10 was down-regulated by the CVB3 infection in the liver, up-regulated in the lungs, but not affected in the pancreas. Accordingly, CVB3 infection increased the concentration of PBDE in the livers of infected mice. However, serum levels of PBDE were not affected by the infection, indicating that serum does not reflect the actual organ exposure of PBDE in infected individuals. The change in metabolising capacity was likely mediated by infection-induced cytokines and associated effects on the nuclear factor-κB (NF-κB) pathway. PBDE drastically decreased serum levels of several cytokines and chemokines, an event that may create a slot for viruses to replicate. Accordingly, some results show that infected mice exposed to a high dose of PBDE had higher virus levels than mice exposed to a low dose. In conclusion, infected individuals showed organ-specific changes in metabolism and tissue levels of PBDE, which potentially could change the toxicity of PBDE. PBDE also seems to affect the fate of the infection. NF-κB activated pathways may mediate one possible mechanism underlying these effects. Thus, further investigations of this pathway are warranted. In addition, future studies should address how PBDE exposure affects viral replication.
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