Within the unregistered compound sets of GSK, Pfizer was considered a potential substitute for addressing the cyclosporin most target. This compound was sourced from Novartis AG, and although it had completed Phase III studies as an oncology drug, it had been discontinued for lack of efficacy. Valspodar did not significantly inhibit and AZ, 15 of the 338 compounds tested showed signifi cant in vitro activity a hit rate of 4. 4%. This higher hit rate in the unregistered compound sets probably reflects the greater diversity of bio activity the SJCRH compound set. The unregistered compounds reflect the focus of recent pharmaceutical development in the companies concerned in anti proliferative, anti infective and anti inflammatory disease, areas likely to have biological over lap with processes in the malaria parasite.

Encouragingly, it is clear that a number of different targets in the malaria parasite can be addressed by existing drugs. For example, several protein kinase inhibitors showed in vitro activity against P. falciparum in this study. These compounds were of particular interest as they are essential throughout all stages of the Plasmodium spp. lifecycle. Many protein kinase inhibitors have been registered or investigated, primarily for the treatment of cancer, although these drugs have known toxicities that have discouraged their use in malaria. Antiretroviral protease inhibitors were also of interest and tested in this study, though they had relatively poor in vitro activity. Previous data showed moderate in vitro activity of saquinavir, nevirapine, ritonavir, nelfi navir, amprenavir, and indinavir at clinically relevant concentrations.

However, a recent clinical study in HIV infected women from malaria endemic regions of sub Saharan Africa showed no effect of antiretroviral treatment on the incidence of malaria. Among the licensed products that were active in vitro, none of the compounds were progressed to the in vivo model, mainly because of their unfavourable pharmacoki netic and/or safety profile for use as an oral anti malarial. However, the scope of this study did not include Drug_discovery specula tion about the clinical safety and pharmacokinetics that might be discovered should clinical studies in malaria be conducted. In fact, a number of these compounds have been investigated further in malaria. Methotrexate has good activity against P. falciparum and Plasmodium vivax in vitro, although poor activity in vivo against murine mal aria species. The assumed toxicity of methotrexate and other anticancer drugs when used in short course, low dose therapy has been questioned. However, a recent clinical study of methotrexate in healthy volunteers failed to achieve sufficient drug exposures for effective malaria therapy.