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 Post subject: On the following day each test article in SFM Trf was 5 fol
PostPosted: Sun Jun 08, 2014 11:58 pm 
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Joined: Mon Nov 18, 2013 9:15 pm
Posts: 176
The lack of convincing efficacy even at high doses coupled with concerns regard ing target selectivity and safety led to a halt in the further investigation of these compounds. Plasmodium falciparum huSCID mouse model The in vivo efficacy of four compounds was determined against P. falciparum in the humanized mouse model. Two of these were identified in screening and two were ABT-888 価格 sourced additionally as a result of findings with related compounds during screening. The most active agent tested was UK 112,214, a water soluble PAF H1 inhibitor identified in the Pfizer STLAR screen. UK 112,214 had an ED90 of 131. 3 mgkg, oral exposure was good, and the pharmacokinetic profile appeared linear within the dosing range. Exposure data from UK 112,214 treated mice versus parasitaemia fitted a sigmoid function.<br><br> The estimated AUCED90 for UK 112,214 was 111. 5 ug h mL−1 day−1. In this model, the ED90 or AUCED90 mark the limit between P. falciparum net growth or net clearance from peripheral blood. Therefore, in order to achieve Afatinib 溶解度 net clearance of P. falciparum from peripheral blood of mice in two cycles of the parasite, a daily expos ure higher than the AUCED90 would be required. A qualitative analysis of the effect of treatment with 300 mgkg UK 122,214 using microscopy and flow cytometry found parasites remaining in periph eral blood 48 hours after the start of treatment. These showed cytoplasmic condensation, vacuolization of trophozoites and absence of mature schizonts. At 96 hours after the start of treatment some pycnotic parasites were also detected.<br><br> These results suggest AG-1478 分子量 that UK 112,214 does not induce fast killing of P. falciparum in peripheral blood. Lestaurtinib is a protein kinase inhibitor thought to target fibroblast growth factor receptor 1, fms like tyrosine kinase 3, tyrosine kinase A and janus kinase 2. A related compound was also provided by Cephalon Inc for testing in the model. These compounds were tested up to the maximum tolerated dose. Although there was a trend for reduced parasitaemia in mice treated with these com pounds, the reduction did not reach statistical significance and ED90 or AUCED90 could not be estimated. For CEP 1347 in the P. falciparum infected mice, the pharmacokinetics after subcutaneous administration in the studied dose range did not appear to be linear, with similar values of Cmax and AUC after the administration of the two selected doses.<br><br> The experimental doses of lestaurtinib were lower than the target ones, but again, non linear pharmacokinetic behaviour was ob served. Note that preclinical studies in mouse cancer models had shown efficacy at exposures similar to those that were achieved in the current study. An additional compound, PSC 833, was tested. This is a non immunosuppressive cyclosporin derivative developed primarily as a p glycoprotein in hibitor. As cyclosporin had been active during in vitro screening against P. falciparum but cannot be considered because of its immunosuppressive properties, valspodar P. falciparum parasitaemia in vivo. The oral pharmacokinetics in the dose range studied was non linear, with similar values of AUC for both dose levels.


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