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Titolo:
Phase I study of intravenous PSC-833 and doxorubicin: Reversal of multidrug resistance
Autore:
Minami, H; Ohtsu, T; Fujii, H; Igarashi, T; Itoh, K; Uchiyama-Kokubu, N; Aizawa, T; Watanabe, T; Uda, Y; Tanigawara, Y; Sasaki, Y;
Indirizzi:
Natl Canc Ctr Hosp E, Dept Med, Div Hematol Oncol, Chiba 2778577, Japan Natl Canc Ctr Hosp E Chiba Japan 2778577 tol Oncol, Chiba 2778577, Japan Novartis Pharma KK, Tsukuba Res Inst, Ibaraki, Osaka 3002611, Japan Novartis Pharma KK Ibaraki Osaka Japan 3002611 raki, Osaka 3002611, Japan Keio Univ, Sch Med, Dept Hosp Pharm, Shinjuku Ku, Tokyo 1608582, Japan Keio Univ Tokyo Japan 1608582 p Pharm, Shinjuku Ku, Tokyo 1608582, Japan
Titolo Testata:
JAPANESE JOURNAL OF CANCER RESEARCH
fascicolo: 2, volume: 92, anno: 2001,
pagine: 220 - 230
SICI:
0910-5050(200102)92:2<220:PISOIP>2.0.ZU;2-I
Fonte:
ISI
Lingua:
ENG
Soggetto:
MDR1A P-GLYCOPROTEIN; BLOOD-BRAIN-BARRIER; SDZ PSC-833; DRUG-RESISTANCE; TISSUE DISTRIBUTION; MULTIPLE-MYELOMA; CYCLOSPORINE-A; CYTO-TOXICITY; VERAPAMIL; MICE;
Keywords:
PSC-833; doxorubicin; pharmacokinetics; pharmacodynamics; multidrug resistance;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
48
Recensione:
Indirizzi per estratti:
Indirizzo: Minami, H Natl Canc Ctr Hosp E, Dept Med, Div Hematol Oncol, 6-5-1 Kashiwanoha, Chiba 2778577, Japan Natl Canc Ctr Hosp E 6-5-1 Kashiwanoha Chiba Japan 2778577 apan
Citazione:
H. Minami et al., "Phase I study of intravenous PSC-833 and doxorubicin: Reversal of multidrug resistance", JPN J CANC, 92(2), 2001, pp. 220-230

Abstract

PSC-833 reverses multidrug resistance by P-glycoprotein at concentrations less than or equal to 1000 ng/ml. A phase I study of PSC-833 and doxorubicin was conducted to determine the maximum tolerated dose and to investigate pharmacokinetics. PSC-833 was intravenously infused as a 2-h loading dose (LD) and a subsequent 24-h continuous dose (CD), Doxorubicin was infused over 5 min, 1 h after the LD, The starting dose was 1 mg/kg for both LD and CDwith 30 mg/m(2) doxorubicin; these dosages were increased to 2 and 10 mg/kg and 50 mg/m(2), respectively. Thirty-one patients were treated. Nausea/vomiting was controllable with granisetron and desamethasone. Neutropenia andataxia were dose limiting. Steady-state concentrations of PSC-833 >1000 ng/ml mere achieved at a 2 mg/kg LD and a 10 mg/kg CD, Ex-vivo bioassay revealed that activity in serum for reversing multidrug resistance was achieved in all patients; IC50 of P-glycoprotein expressing 8226/Dox(6) in patients'serum was decreased from 5.9 to 1.3 mug/ml (P<0.0001) by PSC-833 administration. Doxorubicin clearance was 23.3+/-13.7 (mean+/-SD) liter/h/m(2), which was lower than the 49.0+/-16.9 liter/h/m(2) without PSC-833 (P<0.0001). The relationship between doxorubicin exposure and neutropenia did not differbetween patients treated and not treated with PSC-833, The recommended phase II dose of PSC-833 was 2 and 10 mg/kg for LD and CD, respectively, whichachieved a sufficient concentration in serum to reverse drug resistance, as confirmed by bioassay, The dose of doxorubicin should be reduced to 40 mg/m(2), not because of the pharmacodynamic interaction between PSC-833 and doxorubicin affecting hematopoiesis, but because of pharmacokinetic interaction.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 03/07/20 alle ore 22:37:59