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Titolo:
Safety, toxicokinetics and tissue distribution of long-term intravenous liposomal amphotericin B (AmBisome (R)): A 91-day study in rats
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 Calvert Preclin Serv, Olyphant, PA USA Calvert Preclin Serv Olyphant PA USA vert Preclin Serv, Olyphant, PA USA Amylin Pharmaceut Inc, San Diego, CA USA Amylin Pharmaceut Inc San Diego CA USA Pharmaceut Inc, San Diego, CA USA Biol Serv, Boulder, CO USA Biol Serv Boulder CO USABiol Serv, Boulder, CO 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: 12, volume: 17, anno: 2000,
pagine: 1494 - 1502
SICI:
0724-8741(200012)17:12<1494:STATDO>2.0.ZU;2-U
Fonte:
ISI
Lingua:
ENG
Soggetto:
FUNGAL-INFECTIONS; COLLOIDAL DISPERSION; LIPID COMPLEX; FORMULATION; PHARMACOKINETICS; UNILAMELLAR; ELIMINATION; DELIVERY; TOXICITY; SYSTEM;
Keywords:
amphotericin B; liposomes; pharmacokinetics; toxicokinetics; tissue distribution; toxicity;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
30
Recensione:
Indirizzi per estratti:
Indirizzo: Bekersky, I Fujisawa Healthcare Inc, Deerfield, IL 60015 USA Fujisawa Healthcare Inc Deerfield IL USA 60015 , IL 60015 USA
Citazione:
I. Bekersky et al., "Safety, toxicokinetics and tissue distribution of long-term intravenous liposomal amphotericin B (AmBisome (R)): A 91-day study in rats", PHARM RES, 17(12), 2000, pp. 1494-1502

Abstract

Purpose. Amphotericin B in small, unilamellar liposomes (AmBisome(R)) is safer and produces higher plasma concentrations than other formulations. Because liposomes may increase and prolong tissue exposures. the potential fordrug accumulation or delayed toxicity after chronic AmBisome was investigated. Methods, Rats(174/sex) received intravenous AmBisome (1, 4, or 12 mg/kg). dextrose. or empty liposomes for 91 days with a 30-day recovery. Safety (including clinical and microscopic pathology) and toxicokinetics in plasma and tissues were evaluated. Results. Chemical and histopathologic changes demonstrated that the kidneys and liver were the target organs for chronic AmBisome toxicity. Nephrotoxicity was moderate (urean nitrogen [BUN] less than or equal to 51 mg/ dl: creatinine: unchanged). Liposome-related changes (vacuolated macrophages andhypercholesterolemia) were also observed. Although plasma and tissue accumulation was nonlinear and progressive (clearance and volume decreased, half-life increased with dose and time), most toxic changes occurred early, stabilized by the end of dosing, and reversed during recovery. There were no delayed toxicities. Concentrations in liver and spleen greatly exceeded those in plasma: kidney and lung concentrations were similar to those in plasma. Elimination half-lives were 1-4 weeks in all tissues. Conclusions. Despite nonlinear accumulation. AmBisome revealed predictablehepatic and renal toxicities after 91 days. with no new or delayed effectsafter prolonged treatment at high doses that resulted in plasma levels >200 mug/ml and tissue levels >3000 mug/g.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 16/07/20 alle ore 06:27:25