IGF 1R targeted therapy in RCC was implicated by an early finding of a greater

The assumed toxicity of methotrexate and other anticancer drugs when used in short course, low dose therapy has been questioned. Amuvatinib PDGFR 阻害剤 However, a recent clinical study of methotrexate in healthy volunteers failed to achieve sufficient drug exposures for effective malaria therapy. Methylene blue has also been inves tigated clinically for malaria, although it is slow acting and there are potential haemolytic effects of this compound in glucose 6 phosphate dehydrogenase deficient individuals. Bortezomib has confirmed in vitro activity against P. falciparum, although clinically its effect as an immunosuppressant probably precludes its use in malaria. Similarly, although cyclosporin A has shown good efficacy in a murine mouse model, its immunosuppressive effect prevents its repositioning as an anti malarial.<br><br> Of the non marketed products, four were selected from the test sets for in vivo evaluation and two further drugs were sourced directly from their respective patent owners, CEP 1347 from Cephalon Inc and PSC833 from Novartis Inc. Of these six compounds, only UK 112,214 showed significant activity in vivo. AT-406 UK 112,214 is a water soluble PAF H1 inhibitor targeted for use in allergic inflammatory conditions, such as allergic rhinitis. This is perhaps an unexpected target as clinical studies of the role of PAF in the most severe form of malaria, cerebral malaria, have been inconclusive. However, astemizole, identified as a promising compound for repo sitioning in a previously reported study, is also a PAF H1 inhibitor.<br><br> Of interest is that both UK 112,214 and astemizole have chemical structures related to known anti malarial drugs of the 4 aminoquinoline class and do not, therefore, represent a new class of anti malarial agent. Astemizole was withdrawn because of cardiovascular AG-490 EGFR 阻害剤 adverse events, specifically pro longation of the QT interval caused by potent inhibition of hERG potassium channels. The relative potential for cardiovascular adverse events with UK 112,214 is so far unreported, but an independently run hERG assay sug gests it may too have a cardiac liability. The rate of P. falciparum parasite killing with UK 112,214 was slow, though it could potentially have utility as a combination therapy for the treatment of asexual P. falciparum should sufficient human exposure levels be achieved.<br><br> Unfortunately, there are no human pharma cokinetic data on this compound in the public domain, but single dose pharmacokinetic data provided by Pfizer indicate that UK 112,214 at doses from 10 mg to 480 mg resulted in Cmax values from 14 to 4145 ngml. Safety is the greatest impediment to the repositioning of existing drugs to treat malaria. Anti malarial drugs are taken in possibly many millions of doses every year. Most importantly, an anti malarial must be safe in children indication that is being examined. In particular, artemisinins appear to have many potential uses in di verse indications. Conclusions In recent years, repositioning of existing drug therapy has been suggested as a fast track to developing new anti malarial medicines. Studies such as this are necessary in the continuing efforts to explore all potential routes in the search for new effective medi cines against this devastating disease.