Paclitaxel infusion, prolonged

Meluch AA, Hainsworth JD, Gray JR, et al. Preoperative combined modality therapy with paclitaxel, carboplatin, prolonged infusion 5-fluorouracil, and radiation therapy in localized esophageal cancer preliminary results of a Minnie Pearl Cancer Research Network phase II trial. Cancer J Sci Am 1999 5 (2) 84-91. 

Local venous effects, including erythema, tenderness, and discomfort, can occur at the injection site during paclitaxel infusion (13). Inflammation is evident within hours and usually resolves within 21 days. Inflammation occurs in areas of drug extravasation along with prolonged soft tissue injuries, and necrotic changes have been reported in one patient at the site of extravasation (41). Inflammation is most likely to be due to the drug, but the Cremophor EL vehicle may be implicated, as it produces mild inflammation in animals (41). 

In vitro studies suggested maximum radiosensitization could be achieved by prolonged infusion of paclitaxel (36). A phase I NCI sponsored trial examined the MTD of... 

When paclitaxel was given as short infusion, hypersensitivity reactions typically occurred. Hence, paclitaxel was typically given by prolonged infusion. It was specu-... 

Dose-Densification Using Prolonged Infusion of Paclitaxel... 

In a randomised study, amifostine did not alter the response to, or the phar-maeokineties of, paclitaxel, neither did it protect against paclitaxel-relat-ed neurotoxicity or myelotoxicity. Another study in 8 patients has confirmed that amifostine (750 mg/m as a 15-minute infusion 30 minutes beforehand) had no effect on the pharmacokinetics of paclitaxel 135 to 200 mg/m. Six of the patients were also taking epirubicin and cisplatin. Although the preliminary findings of an earlier study had suggested that pre-treatment with amifostine reduced the AUC of paclitaxel by 29%, the full report of this study concluded that amifostine had no clinically relevant effect on paclitaxel pharmacokinetics. In a study in which patients were given amifostine 500 mg as an infusion over 15 minutes just before low-dose paclitaxel 80 mg/m7 as a one-hour infusion, amifostine reduced maximum plasma levels by about 20%. However, the AUC of paclitaxel was not affected, but the paclitaxel plasma circulation time was prolonged. ... 

Traditionally both saturable distribution and elimination were thought to be the main mechanisms underlying the non-linear pharmacokinetics of paclitaxel [17 ]. However, the formulation vehicle Cremophor EL also has a major effect. The clearance of Cremophor EL increases significantly and disproportionately with prolongation of the infusion [18 , 19 ]. Indeed, unbound paclitaxel has linear pharmacokinetics, with a half-life of about 22 hours [2(T, 2V],... 

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