Lois E. Bolcsak

Activity of paclitaxel liposome formulations against human ovarian tumor xenografts.

Although the current clinical formulation of paclitaxel (Taxol®) is an important new anti‐cancer agent, it has significant side effects, some of which are related to its formulation in Cremophor/ethanol, Paclitaxel is difficult to formulate for i.v. administration because of its poor aqueous solubility. Here, we report the therapeutic effects of 2 liposome formulations of paclitaxel against human ovarian A121 tumor growing as an s.c. xenograft in athymic nude mice. The liposome formulations used were ETL and TTL, which have 1 or 3 lipid components, respectively. TTL was used as a reconstituted lyophilate or as a stable aqueous suspension. ETL was used as a reconstituted lyophilate only. Both paclitaxel‐liposome formulations were much better tolerated than Taxol® after i.v. or i.p. administration. The acute reactions seen after Taxol® administration did not occur when paclitaxel‐liposome formulations were administered. All ETL and TTL preparations significantly delayed A121 tumor growth similarly to Taxol at equivalent doses and schedules. Based on pharmacokinetic data, it is possible that paclitaxel rapidly dissociates from ETL or TTL after i.v. administration and distributes in a manner similarly to Taxol. ETL and TTL formulations may be useful clinically not only for eliminating toxic effects of the Cremophor/ethanol vehicle but also for allowing alterations in route and schedule of drug administration. Int. J. Cancer, 71:103–107, 1997.

A Pharmacokinetic Study of Amphotericin B Lipid Complex Injection (Abelcet) in Patients with Definite or Probable Systemic Fungal Infections

ABSTRACT This study describes a pharmacokinetic evaluation of amphotericin B (AMB) lipid complex injection (ABLC or Abelcet) in 17 patients with systemic fungal infection administered 5 mg/kg of body weight/day by infusion for 10 to 17 days. The results showed that AMB exhibited multiexponential disposition with high clearance, large volume of distribution at steady state, and long apparent elimination half-life but no evidence of accumulation in the blood after multiple daily doses. The results confirm previous observations and further reinforce the suggestion that ABLC may exist as a depot in the tissues from which free AMB is slowly released to limit exposure.

Polymorphic phase behavior of alpha-tocopherol hemisuccinate

Abstract From freeze-fracture electron microscopy and x-ray diffraction we show that α-tocopherol hemisuccinate (α-THS) is capable of polymorphic phase behavior, including the formation of the hexagonal II phase. The transition from bilayer to hexagonal phase was induced by changes in pH, the addition of Ca 2+ , or the inclusion tocopherol. Non-bilayer phases were found to begin below pH 7.5 with hexagonal phase predominating at pH 6.0 and below. The presence of tocopherol at 30 mol% at pH values otherwise favoring the bilayer phase was marked by the appearance of lipidic particles which gave way to purely hexagonal phase at 50 mol%. Ca 2+ added at pH 7.5 induced a complex mixture of dehydrated lamellar and hexagonal II phases. The kinetics of the pH induced transition, as determined by NBD-PE fluorescence and freeze-fracture electron microscopy, were rapid and increased with increasing temperature and decreasing vesicle size.