Antimalarial compounds: from bench to bedside

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Abstract
The emergence and spread of drug-resistant malaria parasites is the major threat to effective malaria control. So far, malaria control has relied heavily on a restricted number of chemically related drugs belonging to either the quinoline or the antifolate groups. Only recently have the artemisinin-type compounds been used widely, predominantly in Southeast Asia. Experience has shown that resistance eventually curtails the life span of antimalarial drugs. If measures are not applied to contain resistance, the investment put into the development of new drugs will be squandered. Current efforts focus, on the one hand, on research into novel compounds with mechanisms of action that are different to the traditionally used drugs, and, on the other hand, on measures to prevent or delay resistance when drugs are introduced. Drug discovery and development are long, risky and expensive ventures. Whilst very few new antimalarial drugs were developed in the last quarter of the 20th century (only four of the nearly 1400 drugs registered worldwide during 1975-1999), various private and public institutions are at work to discover and develop new compounds. Today, the antimalarial pipeline is relatively healthy. Projects are underway at different stages of drug development, from pre-development to registration. However, there is relatively little novelty, as current development projects still rely upon the traditional quinoline, antifolate and, in particular, artemisinin compounds. New structures are expected from the more upstream discovery efforts but it will take time before they become drugs. Therefore, whilst waiting for the drugs of tomorrow, there is a pressing need for immediately available, effective and affordable drugs that will have long life spans. Drug combinations that have independent modes of action are seen as a way of enhancing efficacy while ensuring mutual protection against resistance. Most research work has focussed on the use of artesunate combined with currently used standard drugs, namely mefloquine, amodiaquine, sulfadoxine/pyrimethamine and chloroquine. There is clear evidence that combinations improve efficacy without increasing toxicity. However, the absolute cure rates that are achieved by combinations vary widely and are dependent on the level of resistance of the standard drug. From these studies, further work is underway to produce fixed dose combinations that will be packaged in blister packs. Malaria control programmes need efficacious drugs that can be used with ease by the populations of endemic countries. This review will summarise current antimalarial drug developments and outline recent clinical research that aims to bring artemisinin-based combinations to those that need them most.

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