Comparative in vitro and in vivo evaluation of N-D-ornithyl amphotericin B methyl ester, amphotericin B methyl ester, and amphotericin B.
N-D-Ornithyl amphotericin B methyl ester (O-AME), a semisynthetic derivative of amphotericin B methyl ester (AME), was compared with amphotericin B (AMB) and AME. In vitro, O-AME was more active than the other two against Candida spp. and other fungi and was only slightly affected by inoculum size, addition of serum, or changes in pH. In vivo, the dose of O-AME required to produce a 10,000-fold reduction of Candida albicans in a mouse kidney infection was similar to that of AMB and 1/10 that of AME. After intravenous treatment of infected mice and rats and subcutaneous treatment of mice, average 50% protective doses for O-AME and AMB were similar. Acute intravenous 50% lethal doses in mice indicated that O-AME was one-ninth as toxic as AMB but twice as toxic as AME. Acute renal function tests in rats indicated that Sch 28191 was less than 1/10 as toxic as AMB and slightly more toxic than AME. On this basis, the calculated advantage relative to AMB (with AMB equal to 1) was 8 for O-AME and 1.5 for AME.
Parmegiani
R M
RM
Schering-Plough Corp., Bloomfield, New Jersey 07003.
Loebenberg
D
D
Antonacci
B
B
Yarosh-Tomaine
T
T
Scupp
R
R
Wright
J J
JJ
Chiu
P J
PJ
Miller
G H
GH
D000666:Amphotericin B / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000187:drug effects; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D051381:Rats; D011919:Rats, Inbred Strains
D000935:Antifungal Agents; C017501:methylamphotericin B; C040293:ornithylamphotericin methyl ester; D000666:Amphotericin B