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From page 144... ... 8Drug Discovery and Development WHERE WE WANT TO BE IN THE YEAR 2010 The ready availability of relatively low-cost prophylactic and therapeutic antimalarial drugs will dramatically reverse rising malaria morbidity and mortality evident throughout much of the world. Cooperative efforts among academic, government, and industry researchers will lead to the discovery and development of these new drugs, which will be available in several formulations, effective against all developmental stages of the four human malaria parasites, stable without refrigeration for extended periods, and have few unacceptable side effects. Read the entire page →
From page 145... ... WHERE WE ARE TODAY Principles of Prophylaxis and Treatment There is ample evidence documenting the increasing incidence of malaria worldwide, due in large part to the spread of Plasmodium falciparum. The deteriorating efficacy of existing antimalarial drugs, because of increasing numbers of drug-resistant parasite strains, makes routine prophylaxis and treatment of the disease a therapeutic a challenge. Read the entire page →
From page 146... ... and, in some instances, prophylaxis of these children can be lifesaving. In other situations, however, completely eradicating parasitemia may not be necessary or even desirable. Read the entire page →
From page 147... ... Plasmodium falciparum The situation for drug treatment and prophylaxis of P falciparum malaria is desperate (Payne, 1987; Moran and Bernard, 1989) Read the entire page →
From page 148... ... seriously compromises the therapeutic options for malaria infections acquired in many parts of the world. The choice of a drug of a drug should be guided at least in part by an understanding of the drug sensitivities of the parasites in the locality in which the infection originated. Read the entire page →
From page 149... ... this is an attractive hypothesis, more research in needed to specify the molecular events that underlie the antimalarial activity of primaquine. In addition to its as a causal prophylactic, primaquine has on occasion been used as gametocytocidal drug. Read the entire page →
From page 150... ... The mechanism of action of quinine is not known, nor is it known whether this drug, and others that contain a quinoline nucleus, share a common mechanism. This topic is discussed in more detail for chloroquine, on which most research attention has focused. Read the entire page →
From page 151... ... variants of the lysosomotropic hypothesis, which holds that accumulation of the drug in the acidic food vacuole of the parasite somehow disrupts its function. None of these hypotheses is supported by conclusive proof, and all have been questioned on the basis of experimental results and theoretical consideration (Ginsburg and Geary, 1986; Schlesinger et al., 1988; Geary et al., 1990; Meshnick,1990) Read the entire page →
From page 152... ... when the sulfonamide-containing azodye prontosil was found to be active against P falciparum and the primate malaria parasite P Read the entire page →
From page 153... ... amino acid at one location in dihydrofolate reductase. Proguanil resistance is associated with substitution at a different amino acid location, and strains resistant to both drugs show substitutions at both sites (Peterson et al., 1990) Read the entire page →
From page 154... ... in pregnant women (beyond the first trimester) with falciparum malaria indicate tolerance compatible to that with quinine (World Health Organization, 1990) Read the entire page →
From page 155... ... both support and refute cross-resistance among halofantrine, mefloquine, and quinine have been reported. The mechanism of resistance has not been conclusively proven (Cosgriff et al., 1985; Peter, 1990a) Read the entire page →
From page 156... ... is known to occur in vitro. At least one phenotype appears to be linked to resistance to mefloquine and halofantrine (Peters, 1990b) Read the entire page →
From page 157... ... by various committees of the National Research Council and later the Board for the Coordination of Malaria Studies. This massive, national screening Program allowed for a systematic exploration of certain chemical classes of compounds (Clark, 1946) Read the entire page →
From page 158... ... vitro drug screening using radioisotopes have been developed to complement animal testing in the drug discovery process. Well-characterized clones of falciparum malaria parasites have been derived by a specialized process of direct visualization and single cell micromanipulation. Read the entire page →
From page 159... ... to antimalarial drug screening is WRAIR. Pharmaceutical companies posses collections of compounds which, for the most part, have never been screened for antimalarial activity. Read the entire page →
From page 160... ... better oral bioavailability, and a longer half-life than primaquine. Human testing awaits the filing of an investigational new drug application with FDA. Read the entire page →
From page 161... ... compounds have yet been tested in clinical trials. These drugs may act by blocking the active efflux of chloroquine the parasite, a process that can be measured in vitro (Krogstad et al., 1987) Read the entire page →
From page 162... ... the compound is made available. Studies in clinical pharmacology often lead to better ways of using drugs, better formulations or delivery systems, the optimization of dosing regimens in various populations, and the recognition and alleviation of side effects. Read the entire page →
From page 163... ... falciparum malaria. Although enhanced drug efflux does appear to play a role in this phenomenon, uncertainties remain about the functional mechanism of antimalarial drug resistance. Read the entire page →
From page 164... ... analysis of chloroquine uptake and efflux in resistant strains and development of a convenient assay system of screening candidate antimalarial drugs for P vivax activity. Read the entire page →
From page 165... ... new medically important compounds from microorganisms to the field of antimalarial drug discovery. REFERENCES Arthur, J Read the entire page →
From page 166... ... Geary, T Read the entire page →
From page 167... ... Miller, K Read the entire page →
From page 168... ... synergism and antagonism. Read the entire page →

From page 144...

... 8Drug Discovery and Development WHERE WE WANT TO BE IN THE YEAR 2010 The ready availability of relatively low-cost prophylactic and therapeutic antimalarial drugs will dramatically reverse rising malaria morbidity and mortality evident throughout much of the world. Cooperative efforts among academic, government, and industry researchers will lead to the discovery and development of these new drugs, which will be available in several formulations, effective against all developmental stages of the four human malaria parasites, stable without refrigeration for extended periods, and have few unacceptable side effects.