566C80: a potent broad spectrum anti-infective agent with activity against malaria and opportunistic infections in AIDS patients.
566C80 is a novel hydroxynaphthoquinone with broad-spectrum anti-parasitic properties. In vitro the compound was more potent against Plasmodium falciparum than any of the established anti-malarial drugs. It had good activity against the pathogen in Aotus monkeys and was also effective in rodents infected with various drug-resistant strains of P. yoelii and P. berghei. In mice the compound showed significant activity against Toxoplasma gondii. Evaluation of the metabolic stability of 566C80 to NADPH-mediated oxidative metabolism was made using microsome preparations from a number of species including man. Unlike other quinones examined, 566C80 was shown to be inert in these assays. In Phase 1 clinical studies up to 750mg of compound were given as a single oral dose to fasted healthy male adults. This was well tolerated and the plasma drug elimination half-life was approximately 70h. In these subjects a 450mg dose gave plasma concentrations of 0.1-0.3 micrograms/ml which were achieved 1 h post-dosing and remained so for at least 7 days. Volunteers ingesting food prior to drug administration had quinone plasma levels which were significantly higher. Phase II trials are now underway to assess 566C80 for use against malaria and opportunistic infections in AIDS patients.
Hudson
A T
AT
Wellcome Research Laboratories, Beckenham, Kent, UK.
Dickins
M
M
Ginger
C D
CD
Gutteridge
W E
WE
Holdich
T
T
Hutchinson
D B
DB
Pudney
M
M
Randall
A W
AW
Latter
V S
VS
D042462:4-Quinolones; D000163:Acquired Immunodeficiency Syndrome / Q000150:complications* / Q000188:drug therapy; D000328:Adult; D000818:Animals; D000890:Anti-Infective Agents / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D000962:Antimalarials / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D001029:Aotus trivirgatus; D053626:Atovaquone; D004285:Dogs; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D009249:NADP / Q000378:metabolism; D009285:Naphthoquinones / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D009894:Opportunistic Infections / Q000188:drug therapy* / Q000209:etiology; D010961:Plasmodium / Q000187:drug effects; D051381:Rats; D014122:Toxoplasma / Q000187:drug effects
D042462:4-Quinolones; D000890:Anti-Infective Agents; D000962:Antimalarials; D009285:Naphthoquinones; C075894:298C80; D009249:NADP; C045010:BW 58C; D053626:Atovaquone