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- Lindblom, P, et al.
(författare)
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Tesaglitazar, a dual PPAR-α/γ agonist, hamster carcinogenicity, investigative animal and clinical studies
- 2012
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Ingår i: Toxicologic pathology. - : SAGE Publications. - 1533-1601 .- 0192-6233. ; 40:1, s. 18-32
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Tidskriftsartikel (refereegranskat)abstract
- Tesaglitazar was developed as a dual peroxisome proliferator–activated receptor (PPARα/γ). To support the clinical program, a hamster carcinogenicity study was performed. The only neoplastic findings possibly related to treatment with tesaglitazar were low incidences of hemangioma and hemangiosarcoma in the liver of male animals. A high-power, two-year investigative study with interim necropsies was performed to further elucidate these findings. Treatment with tesaglitazar resulted in changes typical for exaggerated PPARα pharmacology in rodents, such as hepatocellular hypertrophy and hepatocellular carcinoma, but not an increased frequency of hemangiosarcomas. At the highest dose level, there was an increased incidence of sinusoidal dilatation and hemangiomas. No increased endothelial cell (EC) proliferation was detected in vivo, which was confirmed by in vitro administration to ECs. Immunohistochemistry and gene expression analyses indicated increased cellular stress and vascular endothelial growth factor (VEGF) expression in the liver, which may have contributed to the sinusoidal dilatation. A two-fold increase in the level of circulating VEGF was detected in the hamster at all dose levels, whereas no effect on VEGF was observed in patients treated with tesaglitazar. In conclusion, investigations have demonstrated that tesaglitazar does not produce hemangiosarcomas in hamster despite a slight effect on vascular morphology in the liver.
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- Berg, AL, et al.
(författare)
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Early stellate cell activation and veno-occlusive-disease (VOD)-like hepatotoxicity in dogs treated with AR-H047108, an imidazopyridine proton pump inhibitor
- 2008
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Ingår i: Toxicologic pathology. - : SAGE Publications. - 1533-1601 .- 0192-6233. ; 36:5, s. 727-737
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Tidskriftsartikel (refereegranskat)abstract
- Dogs treated with AR-H047108, an imidazopyridine potassium competitive acid blocker (P-CAB), developed clinical signs of hepatic dysfunction as well as morphologically manifest hepatotoxicity in repeat-dose toxicity studies. An investigative one-month study was performed, with interim euthanasia after one and two weeks. A detailed histopathological and immunohistochemical characterization of the liver lesions was conducted, including markers for fibrosis, Kupffer cell activation, apoptosis, and endothelial injury. In addition, hepatic retinoid and procollagen 1α2 mRNA levels in livers of dogs treated with AR-H047108 were analyzed. The results showed an early inflammatory process in central veins and centrilobular areas, present after one week of treatment. This inflammatory reaction was paralleled by activation of stellate/Ito cells to myofibroblasts and was associated with sinusoidal and centrivenular fibrosis. The early activation of stellate cells coincided with a significant decrease in retinyl ester levels, and a significant increase in procollagen 1α2 mRNA levels, in the liver. At later time points (three and six months), there was marked sinusoidal fibrosis in centrilobular areas, as well as occlusion of central veins resulting from a combination of fibrosis and increased thickness of smooth muscle bundles in the vessel wall. The pattern of lesions suggests a veno-occlusive-disease (VOD)–like scenario, possibly linked to the imidazopyridine chemical structure of the compound facilitated by specific morphological features of the dog liver.
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| 10. |
- Danielsson, C, et al.
(författare)
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Is Cardiac Arrhythmia in the Human Embryo a Possible Mechanism for Cardiovascular Defects by I-Kr Blocking Antidepressants? in BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY, vol 91, issue 5, pp 345-345
- 2011
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Ingår i: BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY. - : WILEY-BLACKWELL, COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA. ; , s. 345-345
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Konferensbidrag (refereegranskat)abstract
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| 11. |
- Glinghammar, B, et al.
(författare)
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Proliferative and molecular effects of the dual PPARalpha/gamma agonist tesaglitazar in rat adipose tissues: relevance for induction of fibrosarcoma
- 2011
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Ingår i: Toxicologic pathology. - : SAGE Publications. - 1533-1601 .- 0192-6233. ; 39:2, s. 325-336
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Tidskriftsartikel (refereegranskat)abstract
- The dual peroxisome-proliferator-activated receptor (PPAR) α/γ agonist tesaglitazar has been shown to produce fibrosarcomas in rats. Here, the authors studied morphology, proliferation, differentiation, and inflammation markers in adipose tissue from rats exposed to 1, 3, or 10 µmol/kg tesaglitazar for 2 or 12 weeks, including recovery groups (12 weeks treatment followed by 12 weeks recovery), and 3 or 10 µmol/kg tesaglitazar for 24 weeks. Subcutaneous white and brown fat revealed reversible dose-related histopathological alterations and after 12 and 24 weeks developed areas of thickened skin (fatty lumps). There was a dose-dependent increase in proliferation of interstitial cells in white and brown fat as shown by increased mitotic index in all dose groups after 2 weeks. This was limited to the high dose after 12 and 24 weeks in white fat. Gene expression analyses showed that while tesaglitazar induced differentiation of adipose tissue characterized with a switch in cyclin D1 and D3 mRNA by 12 weeks, longer exposure at high doses reversed this differentiation concurrent with a reappearance of early adipocyte and inflammatory markers. These data suggest that sustained increased turnover of mesenchymal cells in adipose tissues, concomitant with onset of inflammation and fibrosis, drives development of fibrosarcomas in rats treated with tesaglitazar.
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- Skold, A C, et al.
(författare)
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Translational Research: Electrophysiological Development in the Embryonic Heart of Rats, Rabbits, and Humans in BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY, vol 91, issue 5, pp 357-357
- 2011
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Ingår i: BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY. - : WILEY-BLACKWELL, COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA. ; , s. 357-357
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Konferensbidrag (refereegranskat)abstract
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