title: Antimalarial activity of the bicyclic peroxide Ro 42-1611 (arteflene) in experimental models.
abstract: The sesquiterpene peroxide Ro 42-1611 (arteflene), a synthetic derivative of yingzhaosu, was evaluated extensively against various drug-sensitive and drug-resistant lines of Plasmodium falciparum in vitro and P. berghei in vivo in mice. The potential therapeutic and prophylactic activities were studied comparatively with the standard antimalarials chloroquine, mefloquine and quinine, as well as qinghaosu and the derivatives artemether and artesunic acid. Experimentally arteflene proved to be a highly effective antimalarial drug. In vivo it is active at low doses against blood stages of P. berghei in mice after oral or parenteral administration. It has a rapid onset of drug action and a long lasting suppressive effect when given after infection, as well as a good potential for prophylactic activity when given before infection. The suppressive and prophylactic properties are comparable to chloroquine and superior to qinghaosu, artemether and artesunic acid. In vitro the compound showed no signs of cross-resistance with existing antimalarials. It was consistently rather more active against drug-resistant than against drug-sensitive strains of P. falciparum. Drug interaction studies in vitro and in vivo with chloroquine, mefloquine and quinine revealed an additive to synergistic effect with arteflene. Antagonism with these drugs was not observed. Compared with standard antimalarials the activity of arteflene in vitro is lower than would be expected from the in vivo results. This may be due to pharmacokinetic properties of the compound and the formation of an active metabolite which sustains the activity of arteflene in vivo.
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Jaquet
authors.forename: H R
authors.initials: HR
authors.lastname: Stohler
authors.forename: J
authors.initials: J
authors.lastname: Chollet
authors.forename: W
authors.initials: W
authors.lastname: Peters
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D037621:Artemisinins; D001643:Bridged Bicyclo Compounds / Q000627:therapeutic use*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004195:Disease Models, Animal; D004347:Drug Interactions; D006801:Humans; D066298:In Vitro Techniques; D008288:Malaria / Q000188:drug therapy*; D008297:Male; D051379:Mice; D010545:Peroxides / Q000627:therapeutic use; D010962:Plasmodium berghei / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D013343:Styrenes / Q000627:therapeutic use*
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010545:Peroxides; D013343:Styrenes; C090720:arteflene