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Titolo:
Safety and toxicokinetics of intravenous liposomal amphotericin B (AmBisome (R)) in beagle dogs
Autore:
Bekersky, I; Boswell, GW; Hiles, R; Fielding, RM; Buell, D; Walsh, TJ;
Indirizzi:
Fujisawa Healthcare Inc, Deerfield, IL 60015 USA Fujisawa Healthcare Inc Deerfield IL USA 60015 c, Deerfield, IL 60015 USA MDS Harris Labs, Lincoln, NE USA MDS Harris Labs Lincoln NE USAMDS Harris Labs, Lincoln, NE USA Amylin Pharmaceut Inc, San Diego, CA USA Amylin Pharmaceut Inc San Diego CA USA Pharmaceut Inc, San Diego, CA USA NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA NCI Bethesda MD USA 20892 ct, Pediat Oncol Branch, Bethesda, MD 20892 USA
Titolo Testata:
PHARMACEUTICAL RESEARCH
fascicolo: 11, volume: 16, anno: 1999,
pagine: 1694 - 1701
SICI:
0724-8741(199911)16:11<1694:SATOIL>2.0.ZU;2-U
Fonte:
ISI
Lingua:
ENG
Soggetto:
FUNGAL-INFECTIONS; LIPID COMPLEX; FORMULATION; PHARMACOKINETICS; CRYPTOCOCCOSIS; EFFICACY; CANCER; MICE;
Keywords:
amphotericin B; liposomes; pharmacokinetics; tissue distribution; toxicity; toxicokinetics;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
24
Recensione:
Indirizzi per estratti:
Indirizzo: Bekersky, I Fujisawa Healthcare Inc, 3 Pkwy N, Deerfield, IL 60015 USA Fujisawa Healthcare Inc 3 Pkwy N Deerfield IL USA 60015 15 USA
Citazione:
I. Bekersky et al., "Safety and toxicokinetics of intravenous liposomal amphotericin B (AmBisome (R)) in beagle dogs", PHARM RES, 16(11), 1999, pp. 1694-1701

Abstract

Purpose. Amphotericin B (AmB) in small, unilamellar liposomes (AmBisome(R)) has an improved therapeutic index, and altered pharmacokinetics. The repeat-dose safety and toxicokinetic profiles of AmBisome were studied at clinically relevant doses. Methods. Beagle dogs (5/sex/group) received intravenous AmBisome (0.25, 1,4, 8, and 16 mg/kg/day), empty liposomes or vehicle for 30 days. AmB was determined in plasma on days 1, 14, and 30, and in tissues on day 31. Safetyparameters included body weight, clinical chemistry, hematology and microscopic pathology. Results. Seventeen of twenty animals receiving 8 and 16 mg/kg were sacrificed early due to weight loss caused by reduced food intake. Dose-dependent renal tubular nephrosis, and other effects characteristic of conventional AmB occurred at 1 mg/kg/day or higher. Although empty liposomes and AmBisomeincreased plasma cholesterol, no toxicities unique to AmBisome were revealed. Plasma ultrafiltrates contained no AmB. AmBisome achieved plasma levels100-fold higher than other AmB formulations. AmBisome kinetics were non-linear, with clearance and distribution volumes decreasing with increasing dose. This, and nonlinear tissue uptake, suggest AmBisome disposition was saturable. Conclusions. AmBisome has the same toxic effects as conventional AmB, but they appear at much higher plasma exposures. AmBisome's non-linear pharmacokinetics are not associated with increased risk, as toxicity increases linearly with dosage. Dogs tolerated AmBisome with minimal to moderate changes in renal function at doses (4 mg/kg/day) producing peak plasma concentrations of 18-94 mu g/mL.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 16/07/20 alle ore 06:08:04