Wells T.N.,Medicines for Malaria Venture
Discovery medicine | Year: 2010
Malaria kills an estimated one million people a year--mostly children under 5. State-of-the-art medicines known as artemisinin combination therapies (ACTs) are available, and successfully cure up to 99% of patients. Additionally, insecticide-treated bed nets and insecticide spraying are helping to prevent the disease, while a vaccine is in clinical development. With all these tools at hand, you might ask why we need more new medicines. Why not just concentrate on improving the distribution of existing ones? Whilst access to medicines is clearly a major challenge, there are several reasons why new antimalarials are urgently needed--and will continue to be needed until we have finally defeated the parasite. First, the emergence of drug resistance to any infectious disease treatment is inevitable. A range of medicines with varying mechanisms of action are needed to stem the tide of drug resistance as well as fill the gap when it takes hold. Second, malaria is a disease predominantly affecting children and expectant mothers. These vulnerable patient groups require medicines tailored to their needs with robust safety profiles. Third, of the five species of malarial parasites that infect humans, two can relapse, and there is currently no safe medicine to combat the relapse for all patients. Finally, in order to ultimately eradicate malaria, medicines are needed that go a step beyond simple treatment and break the transmission of the parasite from patient to patient. Source
Moehrle J.J.,Medicines for Malaria Venture
British journal of clinical pharmacology | Year: 2013
To assess the safety and pharmacokinetics of a new synthetic ozonide antimalarial, OZ439, in a first-in-man, double-blind study in healthy volunteers. OZ439 was administered as single oral daily doses of a capsule formulation (50-1200 mg) or an oral dispersion (400-1600 mg, fed and fasted states) and for up to 3 days as an oral dispersion (200-800 mg day(-1)). Plasma concentrations of OZ439 and its metabolites were measured by LC-MS. The pharmacokinetic (PK) profile of OZ439 was characterized by a t(max) of around 3 h, followed by a multiphasic profile with a terminal half-life of 25-30 h. 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 t(1/2) 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. 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 Medicines for Malaria Venture (MMV). British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society. Source
Sinden R.E.,University of Oxford |
Carter R.,University of Edinburgh |
Drakeley C.,London School of Hygiene and Tropical Medicine |
Leroy D.,Medicines for Malaria Venture
Malaria Journal | Year: 2012
A meeting to discuss the latest developments in the biology of sexual development of Plasmodium and transmission-control was held April 5-6, 2011, in Bethesda, MD. The meeting was sponsored by the Bill & Melinda Gates Foundation and the National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIH/NIAID) in response to the challenge issued at the Malaria Forum in October 2007 that the malaria community should re-engage with the objective of global eradication. The consequent rebalancing of research priorities has brought to the forefront of the research agenda the essential need to reduce parasite transmission. A key component of any transmission reduction strategy must be methods to attack the parasite as it passes from man to the mosquito (and vice versa). Such methods must be rationally based on a secure understanding of transmission from the molecular-, cellular-, population- to the evolutionary-levels. The meeting represented a first attempt to draw together scientists with expertise in these multiple layers of understanding to discuss the scientific foundations and resources that will be required to provide secure progress toward the design and successful implementation of effective interventions. © 2012 Sinden et al; licensee BioMed Central Ltd. Source
University of Oregon, Medicines For Malaria Venture and University of South Florida | Date: 2013-10-16
Compounds of formula I: or formula II: or a pharmaceutically acceptable salt of formula I or formula II, wherein: R1 is H, hydroxyl, alkoxy, acyl, alkyl, cycloalkyl, aryl, or heteroaryl; R2 is methyl or haloalkyl; R4 is hydroxyl, carbonyloxy, or carbonyldioxy; and R3 is aliphatic, aryl, aralkyl, or alkylaryl; and R5, R6, R7 and R8 are each individually H, halogen, alkoxy, alkyl, haloalkyl, aryl, nitro, cyano, amino, amido, acyl, carboxyl, substituted carboxyl, or SO2R10, wherein R10 is H, alkyl, amino or haloalkyl; provided that in formula I, R5 and R7 are not both H or R6 is not H or methoxy; and in formula II that if R4 is carbonyldioxy then R7 is not methoxy.
The University Of Texas System, Monash University, Glaxosmithkline, University of Washington and Medicines For Malaria Venture | Date: 2010-09-28
Inhibitors of parasitic dihydroorotate dehydrogenase enzyme (DHOD) are candidate therapeutics for treating malaria. Illustrative of such therapeutic agents include the compound: and a triazolopyrimidine class of compounds that conform to Formula IX: and their solvates, stereoisomers, tautomers and pharmaceutically acceptable salts.