Leven M.,Heinrich Heine University Düsseldorf |
Held J.,University of Tübingen |
Duffy S.,Griffith University |
Tschan S.,University of Tübingen |
And 14 more authors.
Journal of Medicinal Chemistry | Year: 2014
3-Hydroxy-N-arylidenepropanehydrazonamides represent a new class of antiplasmodial compounds. The two most active phenanthrene-based derivatives showed potent in vitro antiplasmodial activity against the 3D7 (sensitive) and Dd2 (multidrug-resistant) strains of Plasmodium falciparum with nanomolar IC50 values in the range of 8-28 nM. Further studies revealed that the most promising derivative, bearing a 4-fluorobenzylidene moiety, demonstrated in vivo antiplasmodial activity after oral administration in a P. berghei malaria model, although no complete parasite elimination was achieved with a four-dose regimen. The in vivo efficacy correlated well with the plasma concentration levels, and no acute toxicity symptoms (e.g., death or changes in general behavior or physiological activities) were observed, which is in agreement with a >1000-fold lower activity against L6 cells, a primary cell line derived from mammalian (rat) skeletal myoblasts. This indicates that lead compound 29 displays selective activity against P. falciparum. Moreover, both phenanthrene-based derivatives were active against stage IV/V gametocytes of P. falciparum in vitro. © 2014 American Chemical Society.
Moehrle J.J.,Medicines for Malaria Venture |
Duparc S.,Medicines for Malaria Venture |
Siethoff C.,Swiss BioQuant |
van Giersbergen P.L.M.,Swiss BioQuant |
And 6 more authors.
British Journal of Clinical Pharmacology | Year: 2013
Aims: To assess the safety and pharmacokinetics of a new synthetic ozonide antimalarial, OZ439, in a first-in-man, double-blind study in healthy volunteers. Methods: OZ439 was administered as single oral daily doses of a capsule formulation (50-1200mg) or an oral dispersion (400-1600mg, fed and fasted states) and for up to 3 days as an oral dispersion (200-800mg day-1). Plasma concentrations of OZ439 and its metabolites were measured by LC-MS. Results: The pharmacokinetic (PK) profile of OZ439 was characterized by a tmax of around 3h, followed by a multiphasic profile with a terminal half-life of 25-30h. The PK parameters were approximately dose proportional for each group and profiles of the metabolites followed a similar pattern to that of the parent compound. Following dosing for 3 days, accumulation was less than two-fold but steady-state was not achieved. In the presence of food, no effect was observed on the t1/2 of OZ439 while the exposure was increased by 3 to 4.5-fold. Exposure was higher and inter-subject variability was reduced when OZ439 was administered as an oral dispersion compared with a capsule. The urinary clearance of OZ439 and its metabolites was found to be negligible and OZ439 did not induce CYP3A4. The antimalarial activity profiles of a subset of serum samples suggested that the major antimalarial activity originated from OZ439 rather than from any of the metabolites. Conclusion: The safety and pharmacokinetic profile of OZ439 merits progression to phase 2a proof of concept studies in the target population of acute uncomplicated malaria. © 2012 The British Pharmacological Society.
Cobb Z.,Quotient Bio Analytical science Part of the LGC Group |
De Vries R.,Janssen R and D |
Spooner N.,Glaxosmithkline |
Williams S.,Charles River Laboratories |
And 12 more authors.
Bioanalysis | Year: 2013
Background: At the start of their work, the European Bioanalysis Forum dried blood spots microsampling consortium did not form a dedicated team to investigate the spot homogeneity. However, two teams performed experiments that produced results relating to sample homogeneity. Results: The data, which were produced via two different approaches (a radiolabeled and a nonradiolabeled approach), are highly complementary and demonstrate clear effects on sample inhomogeneity due to the substrate type, compound and hematocrit levels. Conclusion: The results demonstrate that sample inhomogeneity is a significant hurdle to the use of dried blood spots for regulated bioanalysis that should be investigated further in the method establishment phase if the whole spot is not sampled. © 2013 Future Science Ltd.
De Vries R.,Janssen R and D NV |
Barfield M.,Glaxosmithkline |
Van De Merbel N.,PRA |
Schmid B.,Nuvisan GmbH |
And 7 more authors.
Bioanalysis | Year: 2013
Background: The European Bioanalysis Forum dried blood spots (DBS)/microsampling consortium is reporting back from the experiments they performed on further documenting the potential hurdles of the DBS technology. This paper is focused on the impact of hematocrit changes on DBS analyses. Results: The hematocrit can have an effect on the size of the blood spot, on spot homogeneity and on extraction recovery in a compound-dependent manner. The extraction recovery can change upon aging in an hematocrit-dependent way. Different card materials can give different outcomes. Conclusions: The results from the conducted experiments show that the issues of DBS in regulated bioanalysis are real and that the technology will need improvements to be ready for use as a general tool for regulated bioanalysis. © 2013 Future Science Ltd.