naphthoquinones and artemisin

Understanding the mode of action of and mechanism of resistance to drugs is central to optimising their use, and discovering new therapeutics with novel targets. We have limited understanding of how antimalarial drugs work and how resistance emerges. With few exceptions, antimalarial drugs in current use belong to a limited collection of chemical structures that act on a small number of partially characterised biochemical targets. Resistance has emerged to many of these compounds. The use of closely related compounds has promoted the spread of multidrug resistant parasites. This review intends to collate contemporary knowledge, and also to highlight conflicting views on unresolved issues.

Topics: Animals; Antimalarials; Artemisinins; Atovaquone; Drug Resistance; Drug Therapy, Combination; Folic Acid Antagonists; Humans; Lactones; Mutation; Naphthoquinones; Nucleic Acids; Plasmodium; Proguanil; Quinolines; Sesquiterpenes

The anticryptosporidial activity of four macrolides alone and in combination with other antimicrobial agents was investigated against ten clinical isolates of Cryptosporidium parvum recovered from stools of AIDS patients. The susceptibility tests were performed by inoculation of the protozoa on to cell monolayers and determining the parasite count after 72 h incubation at 37 degrees C. The culture medium was supplemented with Dulbecco's modified Eagle's medium containing serial dilutions of azithromycin, clarithromycin, roxithromycin, spiramycin, alone or in combination with artemisin, atovaquone, dapsone, minocycline or pyrimethamine. Most of the agents had an inhibitory effect on parasite growth, but only at high concentrations. No agent was able to inhibit parasite growth completely, even at the highest concentrations used. The more effective agents, azithromycin, clarithromycin, roxithromycin, minocycline and pyrimethamine, produced no more than a 13.1-27.8% reduction in oocyst count and no more than a 15.1-35.7% in schizont count. Positive interaction was clearly demonstrated when macrolides were tested in combination with minocycline or pyrimethamine.

Topics: Acquired Immunodeficiency Syndrome; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Artemisinins; Atovaquone; Cryptosporidiosis; Cryptosporidium parvum; Dapsone; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Lactones; Macrolides; Minocycline; Naphthoquinones; Pyrimethamine; Sesquiterpenes

A series of Plasmodium falciparum in vitro drug sensitivity studies were conducted in order to evaluate atovaquone in combination with other antimalarial drugs and thus to identify a potential partner for a fixed combination. The derived isobolograms indicated that drug interactions ranged from antagonism through addition to synergy. Of particular note were the quinolines and artemisinin analogues, which were all antagonistic, and the biguanides and tetracycline, which showed synergy. Proguanil emerged as the most promising of the current antimalarials as a partner for atovaquone in a fixed combination, with tetracycline as back-up.

Topics: Animals; Antimalarials; Artemisinins; Atovaquone; Drug Interactions; Lactones; Naphthoquinones; Plasmodium falciparum; Proguanil; Quinolines; Sesquiterpenes; Tetracycline