A New High-performance Liquid Chromatographic Method for Fludarabine and Fludarabine Phosphate Compounded in Liposomes.

A simple and reproducible high-pressure liquid chromatography (HPLC) method was developed to measure simultaneously the concentrations of both fludarabine and liposome-compounded fludarabine in plasma. In this method, hypoxanthine 9-B-D arabinofuranoside was used as an internal standard. Fludarabine, fludarabine phosphate, and hypoxanthine 9-B-D arabinofuranoside were extracted from plasma and were separated by means of isocratic elution from a C18 reversed-phase column. The mobile phase consisted of 5% (v/v) methanol in 10mM ammonium phosphate solution. The pH of the mobile phase was adjusted to 2.2 with 85% phosphoric acid. The detection wavelength was 260 nm, and the retention times for fludarabine, fludarabine phosphate, and hypoxanthine 9-B-D arabinofuranoside were 48, 27, and 12 minutes, respectively. The recovery efficiencies varied depending on the amount spiked; however, they were 89% and 58% for 10 micrograms/mL of fludarabine and fludarabine phosphate, respectively. The limits of quantification for fludarabine and fludarabine phosphate were 0.03 micrograms/mL and 0.5 micrograms/mL, respectively. The assay was reproducible, and the within-day coefficients of variation (n=4) were less than 6.9% and less than 8.7% for fludarabine and fludarabine phosphate, respectively. The between day variabilities (n=4) were less than 6.3% and less then 6.4% for fludarabine and fludarabine phophate, respecitvley. The assays were linear within the range of 0.025 to 10 micrograms/mL (r squared = 0.999) for fludarabine and 0.5 to 10 micrograms/mL (r squared = 0.999) for fludarabine phosphate.

Efficacy and safety of oral granisetron versus i.v. granisetron in patients undergoing peripheral blood progenitor cell and bone marrow transplantation.

This randomized, controlled, double-blind pilot study assessed the efficacy and safety of oral versus i.v. granisetron, both in combination with non-5-HT3 antiemetics, in preventing emesis caused by high-dose chemotherapy. Fifty-one patients who underwent peripheral blood progenitor cell transplantation (PBPCT) or bone marrow transplantation (BMT) were evaluated. Efficacy was assessed by the number of emetic episodes during the worst 24 h period. A complete response (CR) was defined as no vomiting, partial response (PR) as less than three emetic episodes and failure as three or more emetic episodes. Patients who received oral granisetron experienced significantly (p<0.0008) fewer emetic episodes than those who received i.v. granisetron; however, the number of emetic episodes over the worst 24 h was similar between the oral and i.v. granisetron groups (13 and 15, respectively), as were the overall response rates (CR+PR, 54.5 and 41.4%, respectively). Both dosage forms were well tolerated. Based on these findings, further comparative studies of oral granisetron are warranted in patients undergoing PBPCT or BMT.

The clinical pharmacology of topoisomerase I inhibitors.

The Chinese tree Camptotheca acuminata, or Xi Shu, brings us a unique class of chemotherapeutic agents known as the camptothecins. Because the parent compound exhibited excessive toxicity and poor aqueous solubility, synthetic and semisynthetic analogs were developed. These compounds contain a lactone ring that is necessary for activity and is easily hydrolyzed into the less active hydroxy carboxylic acid. Irinotecan, a semisynthetic analog is a prodrug that is cleaved by a carboxylesterase-converting enzyme to form the biologically active metabolite SN-38. The half-lives of irinotecan and SN-38 are relatively long, and both are commonly found in the lactone form. Topotecan differs from irinotecan in that it is found predominately in the inactive carboxylate form at neutral pH, but can be maintained in the lactone form at a lower pH. In phase I clinical trials, the antitumor activity of topotecan has been impressive. In vitro and in vivo studies have shown that combinations between topotecan and 5-fluorouracil or cisplatin have synergistic antitumor effects compared with topotecan alone. Two relatively new agents, 9-aminocamptothecin and GG211, have produced promising results against a variety of tumors.