Mapping antimalarial pharmacophores as a useful tool for the rapid discovery of drugs effective in vivo: design, construction, characterization, and pharmacology of metaquine.

Resistant strains of Plasmodium falciparum and the unavailability of useful antimalarial vaccines reinforce the need to develop new efficacious antimalarials. This study details a pharmacophore model that has been used to identify a potent, soluble, orally bioavailable antimalarial bisquinoline, metaquine (N,N'-bis(7-chloroquinolin-4-yl)benzene-1,3-diamine) (dihydrochloride), which is active against Plasmodium berghei in vivo (oral ID(50) of 25 micromol/kg) and multidrug-resistant Plasmodium falciparum K1 in vitro (0.17 microM). Metaquine shows strong affinity for the putative antimalarial receptor, heme at pH 7.4 in aqueous DMSO. Both crystallographic analyses and quantum mechanical calculations (HF/6-31+G) reveal important regions of protonation and bonding thought to persist at parasitic vacuolar pH concordant with our receptor model. Formation of drug-heme adduct in solution was confirmed using high-resolution positive ion electrospray mass spectrometry. Metaquine showed strong binding with the receptor in a 1:1 ratio (log K = 5.7 +/- 0.1) that was predicted by molecular mechanics calculations. This study illustrates a rational multidisciplinary approach for the development of new 4-aminoquinoline antimalarials, with efficacy superior to chloroquine, based on the use of a pharmacophore model.

A randomized trial of two public health nurse follow-up programs after early obstetrical discharge: an examination of breastfeeding rates, maternal confidence and utilization and costs of health services.

OBJECTIVES: To determine whether the outcomes of routine home visiting by public health nurses (PHN) after early obstetrical discharge differ from those of a screening telephone call designed to identify mothers who need further intervention. METHODS: Primiparas delivering a singleton infant and eligible for postpartum follow-up were randomized to a home visit or screening telephone call. Data were collected by telephone from 733 participants located at two tertiary care centres in Ontario. Outcomes included maternal confidence at two weeks, health problems of the infants between discharge and four weeks postpartum, breastfeeding rates at six months and costs of the two models. RESULTS: Differences between the samples at the two sites necessitated stratified analyses. No differences were detected between the groups in maternal confidence (p = 0.96), health problems of infants (p = 0.87), or rates of breastfeeding at six months (p = 0.22). However, at both sites the cost of routine home visits was found to be higher than that of screening by telephone. CONCLUSION: Although universal access to postpartum support is important, the results suggest that a routine home visit is not always necessary to identify the women who need it. These results can be generalized only to low-risk women and infants.