falciparum net growth or net clearance from peripheral blood. Therefore, in order to achieve net clearance of P. falciparum from peripheral blood of mice in two cycles of the parasite, a daily expos ure higher inhibitor Pfizer than the AUCED90 would be required. A qualitative analysis of the effect of treatment with 300 mg/kg 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. These results suggest 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. 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. In programmes that are currently being conducted in collaboration with or supported by MMV, a significant in vivo potency in the humanized mouse model is consid ered to be lower than 20 mg/kg.

Therefore, none of the drugs tested met the criteria for further development. Discussion Although a large number of approved, investigational and discontinued drugs were evaluated in this project, none of the compounds identified with antiplasmodial activity met the candidate selection criteria warranting further development. From the approximately 3,800 compounds that were tested by SJCRH, there were 24 with EC50 values Carfilzomib 1 uM against P. falciparum a hit rate of about 0.