| 1. |
- 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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| 2. |
- Olsén, Lena, et al.
(author)
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Pharmacokinetics and effects of cetirizine in horses with insect bite hypersensitivity
- 2011
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In: The Veterinary Journal. - : Elsevier BV. - 1090-0233 .- 1532-2971. ; 187:3, s. 347-351
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Journal article (peer-reviewed)abstract
- Horses with insect bite hypersensitivity (IBH) have difficulty in completely avoiding allergens, so effective treatment options are required. A randomised, placebo controlled and double blinded field study was conducted to determine the pharmacokinetics and efficacy in reducing dermatitis of the antihistamine cetirizine given orally at 0.4mg/kg twice daily for 3weeks. The influence of protection blankets and stabling were also investigated. The estimated maximum plasma concentration (C(max)) and trough plasma concentration of cetirizine were 135ng/mL and 18ng/mL, respectively. There was no difference in dermatitis reduction between the treatment and placebo groups (P=0.77). The findings indicated that cetirizine was of no apparent benefit in treating IBH at the dose rate tested. The use of blankets and stabling were shown to have favourable influence on the dermatitis (P<0.05) and may be the preferred options to prevent this condition.
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| 3. |
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| 4. |
- Carlsson, Carina
(author)
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Neurotoxic Effects of Dichlorophenyl Methylsulphones Related to Olfactory Mucosal Lesions
- 2003
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Doctoral thesis (other academic/artistic)abstract
- This thesis deals with the highly potent olfactory mucosa toxicant 2,6-dichlorophenyl methylsulphone (2,6-diClPh-MeSO2) and its non-toxic 2,5-chlorinated isomer (2,5-diClPh-MeSO2). In mice, both substances bind firmly in the olfactory mucosa and the olfactory bulb, which are important components of the sensory system. The 2,6-isomer induces olfactory mucosal necrosis with permanent loss of olfactory neuroepithelium and olfactory nerves. A major objective was to clarify the cause of this isomer-specific toxicity, and to identify which physicochemical characteristics determine the olfactory toxicity. The neurobehavioural toxicity of these substances was also examined.The results revealed a rapid CYP-catalysed covalent binding of 2,6-diClPh-MeSO2 in the rat olfactory mucosa, whereas the 2,5-dichlorinated isomer was not covalently bound.Acute and chronic olfactory mucosal pathology were investigated and compared in rats and mice. Twenty-four hours after dosing to rats, 2,6-diClPh-MeSO2 induced Bowman’s glands necrosis and sloughing of the olfactory epithelium similar to that previously reported in mice. At 3 weeks, however, there were dramatic differences in histological lesions. In mice, large parts of olfactory epithelium were replaced by respiratory-like epithelium. Large, bilateral, fibrous, cartilage and bone containing polyps occluding the lumen were confirmed. In rats, only minor patches of olfactory epithelium were replaced by a metaplastic atypical respiratory-like epithelium. 2,5-diClPh-MeSO2 was non-toxic in rats as well as in mice.In mice, 2,6-diClPh-MeSO2 induced a dose-dependent and long-lasting ( ≥12 weeks) hyperactivity as well as long-lasting maze learning deficits. At 2 weeks hyperactivity and maze learning deficits were observed also in rats. Unexpectedly, 2,5-diClPh-MeSO2 induced hyperactivity that lasted for two weeks. No effect on maze learning was observed with this isomer. No major differences between male and female rats or mice were found.In conclusion, the results show that a CYP-catalysed formation and covalent binding of a reactive 2,6-diClPh-MeSO2-metabolite in the Bowman’s glands precede the high olfactory mucosal toxicity in rodents. As determined by QSAR-modelling, a 2,6-dichlorinated benzene derivative with a large, polar, and strong electron withdrawing substituent in the primary position has the potential of being an olfactory mucosal toxicant. The observed 2,6-diClPh-MeSO2-induced increase in motor activity, and maze learning deficits, were not correlated to the olfactory mucosal lesions. I propose that 2,6-diClPh-MeSO2 causes a direct effect in the brain leading to neurobehaviuoral deficits.
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| 5. |
- 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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| 6. |
- 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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| 7. |
- Stridsberg, Mats, et al.
(author)
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Whole-body autoradiography of 123I-labelled islet amyloid polypeptide (IAPP) Accumulation in the lung parenchyma and in the villi of the intestinal mucosa in rats
- 1993
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In: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 32:2, s. 155-9
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Journal article (other academic/artistic)abstract
- Islet amyloid polypeptide (IAPP) in a 37 amino-acid pancreatic islet polypeptide, displaying about 50% amino-acid homology with neuropeptide calcitonin gene-related peptide (CGRP). IAPP is co-stored with insulin in the beta-cell secretory granules and co-released with insulin upon stimulation. Human IAPP has the ability to precipitate in the shape of amyloid in patients with type II (non-insulin dependent) diabetes but otherwise its functional or pathophysiological role is enigmatic. In the present study 125I-labelled rat IAPP was injected i.v. into female Sprague-Dawley rats and the distribution of the peptide was examined by whole-body autoradiography at intervals from 2 to 30 min after administration. Already after 2 min high radioactivity occurred in the lung parenchyma and in the villi of the small intestinal mucosa. The high radioactivity in these tissues persisted at 10 min but at 30 min the radioactive labelling had decreased to a level only slightly higher than that observed in the blood. A high uptake of radioactivity was also seen in the cortex of the kidney. In other tissues, including the liver, the skeletal muscle, and the exocrine and endocrine pancreas, the radioactivity was low and did not exceed that of the blood. The uptake of 125I-IAPP in the lungs and in the small intestine was inhibited by simultaneous injections of either an excess of unlabelled rat IAPP or unlabelled rat CGRP. This indicates that the labelled structures observed in the lung and the small intestine after injection of 125I-IAPP alone was due to binding to receptors for IAPP or CGRP in these tissues. The accumulation of radioactivity in the kidneys was not affected by pretreatment with high doses of unlabelled IAPP or CGRP. This unspecific uptake of radioactivity may be due to reabsorption of labelled IAPP in the proximal tubuli. Our results indicate the presence of receptors binding IAPP in the lung parenchyma and in the villi of the small intestinal mucosa. This, in turn, may imply prominent biological activities of IAPP at these sites.
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