Antimalarial drugs have usually been first deployed in areas of malaria endemicity at doses which were too low, particularly for high-risk groups such as young children and pregnant women. This may accelerate the emergence and spread of resistance, thereby shortening the useful life of the drug, but it is an inevitable consequence of the current imprecise method of dose finding. An alternative approach to dose finding is suggested in which phase 2 studies concentrate initially on pharmacokinetic-pharmacodynamic (PK-PD) characterization and in vivo calibration of in vitro susceptibility information. PD assessment is facilitated in malaria because serial parasite densities are readily assessed by microscopy, and at low densities by quantitative PCR, so that initial therapeutic responses can be quantitated accurately. If the in vivo MIC could be characterized early in phase 2 studies, it would provide a sound basis for the choice of dose in all target populations in subsequent combination treatments. Population PK assessments in phase 2b and phase 3 studies which characterize PK differences between different age groups, clinical disease states, and human populations can then be combined with the PK-PD observations to provide a sound evidence base for dose recommendations in different target groups.
No abstract is provided for this article.
EDITOR—The paper by Plowe et al entitled “Sustained clinical efficacy of sulfadoxine-pyrimethamine for uncomplicated falciparum malaria” might be better titled “Sustained lack of efficacy of sulfadoxine-pyrimethamine….”1 By the start of the study period five years ago, molecular genotyping showed that Plasmodium falciparum in Malawi had already acquired significant resistance to the combination.1 2 This explains the sustained lack of efficacy; …
The ability to discriminate between conspecifics functions in mate choice, kin-selected cooperation and territory defence. In mammals, olfaction plays a key role in such social interactions. Olfactory cues may be particularly important for subterranean mammals, for which visual and acoustic cues are less effective. Damaraland mole-rats live in groups comprising a breeding pair and their nonbreeding offspring. They are xenophobic, obligate outbreeders and independent dispersal represents the usual route to reproduction for both sexes. As yet, little is known about how dispersing individuals locate mates. Using a series of behavioural experiments, we reveal that mole-rats can discriminate between unfamiliar breeding groups and solitary, nonbreeders of the opposite sex by using odour cues. Our experiments showed that subjects spent more time investigating sand taken from other mole-rat groups than control sand, indicating an ability to recognize substrate-borne conspecific odours. Mole-rats also spent more time digging and sweeping in sand taken from the tunnels of unfamiliar, solitary animals of the opposite sex than sand taken from unfamiliar breeding groups and removed a higher volume of this sand during the experiments. Together, these results suggest an olfactory preference in both sexes for solitary, opposite-sex animals over breeding groups. Our results are supported by observations from the field that immigration into breeding groups is rare, with dispersing females typically establishing new groups, where they are subsequently joined by unfamiliar males. This study supports olfaction as a potential recognition cue which may facilitate adaptive dispersal.
