title: Evaluation of the efficacy and toxicity of amphotericin B incorporated in lipid nano-sphere (LNS).
abstract: To develop a low-dose therapeutic system for amphotericin B (AmB), the efficacy and toxicity of lipid nano-sphere (LNS) incorporating AmB (LNS-AmB) were evaluated and compared with those of Fungizone, the conventional dosage form of AmB with sodium deoxycholate. LNS-AmB and Fungizone showed nearly equal activity against fungal cells both in vitro and in vivo. In contrast to Fungizone, however, LNS-AmB did not cause significant hemolysis. In addition, the vomiting toxicity of Fungizone was largely avoided by the use of LNS-AmB in dogs, in spite of the higher plasma AmB concentrations achieved by LNS-AmB. Therefore, LNS-AmB may be selective for fungal cells over mammalian cells. In a study of its toxicity and toxicokinetics in a regimen of daily 2-h intravenous infusions for 14 consecutive days, LNS-AmB showed less toxicity to the kidney than did Fungizone in spite of the higher plasma AmB concentrations achieved. LNS-AmB, therefore, allows the treatment of systemic fungal infections at low doses without the severe nephrotoxicity of Fungizone. Size-exclusion chromatography provided evidence that, when LNS-AmB was administered to rats, AmB was retained in the LNS particles in the blood circulation, but that when Fungizone was administered, AmB was transferred to high-density lipoproteins (HDL). AmB retained in LNS particles seemed to be less toxic to the kidney than was AmB associated with HDL. Consequently, LNS-AmB has the potential to become a low-dose therapeutic system for AmB, minimizing most of the severe side effects of AmB by decreasing the total dose required.
authors.affiliation: R&D Administration Department, Nippon Shinyaku Co. Ltd., 14, Nishinosho-Monguchi-cho, Kisshoin, Minami-ku, Kyoto 601-8550, Japan. h.fukui@po.nippon-shinyaku.co.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukui
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Koike
authors.forename: Akira
authors.initials: A
authors.lastname: Saheki
authors.forename: Satoru
authors.initials: S
authors.lastname: Sonoke
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Tomii
authors.forename: Junzo
authors.initials: J
authors.lastname: Seki
mesh_terms: D000666:Amphotericin B / Q000008:administration & dosage* / Q000097:blood / Q000633:toxicity*; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D008055:Lipids / Q000008:administration & dosage* / Q000097:blood; D008297:Male; D051379:Mice; D043942:Nanotubes; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D008055:Lipids; D000666:Amphotericin B