Chantal Laduron

Pilot study of amphotericin B entrapped in sonicated liposomes in cancer patients with fungal infections

A pilot study with amphotericin B incorporated in sonicated liposomes (ampholiposomes) made of egg phosphatidylcholine, cholesterol and stearylamine in a molar ratio 4:3:1 was performed in cancer patients with fungal infections. Fifteen patients received a total of 117 intravenous infusions of ampholiposomes. The total dose of amphotericin B administered per patient ranged from 20 to 1004 mg (mean 472 mg). The number of infusions per patient varied from 1 to 20 (mean 8) and the duration of treatment from 1 to 29 days (mean 10 days). Infusion of doses up to 1.8 mg/kg was well tolerated. None of the common side-effects of Fungizone, the colloidal suspension of amphotericin B, occurred; it was noteworthy that patients had no renal function impairment. Serum amphotericin B concentrations given as ampholiposomes were much higher than those obtained with Fungizone. With a daily treatment schedule, peak and trough serum amphotericin B concentrations, as measured by HPLC, were 10 to 20 micrograms/ml and 5 to 10 micrograms/ml respectively; while they did not exceed 2 micrograms/ml and 1 microgram/ml with Fungizone. Amphotericin B given as ampholiposomes had a prolonged serum beta half-life (25.3 +/- 16.0 h). Higher serum antifungal activity was observed with ampholiposomes as compared to Fungizone. We concluded that ampholiposomes have a better therapeutic index than Fungizone.

Intravenous infusion of high doses of liposomes containing NSC 251635, a water-insoluble cytostatic agent. A pilot study with pharmacokinetic data.

In patients with resistant malignant tumors, we performed a pilot trial of intravenous infusion of a water-insoluble cytostatic agent, NSC 251635, entrapped in large volumes of liposomes made of egg yolk lecithin, cholesterol, and stearylamine (4:3:1). Forty liposome infusions were given to 14 patients in 38 courses. The volume of liposomes (20 mg of lipids/mL) varied from 205 to 1,000 mL or 124 to 617 mL/m2 of body surface, and amounts of NSC 251635 varied from 82 to 456 mg/m2. Three patients received repeated single courses. Liposomal therapy was very well tolerated. Side effects observed during some infusions were mild sedation, fever, chills, lumbar pain, urticarial rash, and bronchospasm. In all patients investigated, an important activation of the complement system was observed. No objective regression of the tumors was observed. The limiting factor in the phase I study was not toxicity but the volume of liposomes that could be prepared at once because of the long time required for its preparation. Pharmacokinetic data showed that maximal serum phospholipid and NSC 251635 concentrations were obtained at the end of the liposome infusion. The drugs peak was followed by a decreasing phase leading to a kind of plateau and a prolonged presence of the drug in the blood until 120 hours after its administration. Comparison of the pharmacokinetics of phospholipids and NSC 251635 suggests a rather rapid dissociation of the drug from the liposome.

Pharmacokinetics of Amphotericin B in Patients Receiving Repeated Intravenous High Doses of Amphotericin B Entrapped into Sonicated Liposomes

AbstractRepeated high doses (2-4 mg/kg/day) of amphotericin B entrapped in sonicated liposomes made of egg yolk lecithin, cholesterol, and stearylamine in the molar ratio 4:3:1 were given intravenously to cancer patients with fungal complications. High levels of the drug were measured in the serum. Pharmacokinetic analysis showed that amphotericin B distribution followed a nonlinear bicompartmental model incorporating a liposome-free drug subsystem. This model allowed us to define the Michaelis-Menten dissociation constant of uptake of the drug entrapped in the liposomes by the storage compartment, the maximal liberation rate and fractional liberation rate of free amphotericin B, and the number of binding sites in the ampholiposome storage compartment. the levels of free amphotericin B in the serum and the kinetics of saturation of the uptake of ampholiposomes by the storage compartment were also calculated.

Phase I Study, with Pharmacokinetic Analysis, of Intravenous Administration of 6-Aminochrysene Entrapped into Sonicated Liposomes in Patients with Advanced Cancer

AbstractA phase I study of the intravenous administration of a water-insoluble cytostatic agent, 6-aminochrysene, was performed by using as carriers sonicated liposomes made of egg yolk lecithin, cholesterol, and stearylamine in the molar ratio 4:3:1. Thirteen patients were included in this trial and 47 infusions of liposomes were given. Dosages of 6-aminochrysene per course were escalated from 30 mg/m2 to 200 mg/m2. Courses were repeated every 2 weeks. No limiting toxicity was reached. Tolerance was good. Only slight sedation, nausea and vomiting, venous irritation, and lumbar pain were observed in a few patients. the maximum volume of liposomes infused over 2 hr was 1,196 ml. An objective response with regression of brain and adrenal metastases was observed in a patient with non-small-cell lung cancer. Pharmacokinetic analysis showed that the 6-aminochrysene serum concentration profiles were best fitted by a linear bicompartmental model. This study confirms that sonicated liposomes made of egg yolk leci...

Chemotherapeutic efficacy of Nocodazole encapsulated in liposomes on L1210 murine leukemia.

The use of sonicated phospholipid vesicles (liposomes) as carriers of methyl [5-(2-thienylcarbonyl)-1H-benzimidazol-2-yl] carbamate (Nocodazole), a water insoluble antimitotic compound active on mouse L1210 leukemia was investigated. Nocodazole was incorporated in dipalmitoyl-phosphatidylcholine: cholesterol: stearylamine (4:3:1) liposomes that were stable at room temperature for at least 48 hr. No drug leakage nor lipid exchange occurred after a 4 hr incubation at 37 degrees C with RPMI 1640 medium supplemented with 10% fetal calf serum. L1210 cells preincubated (2 x 10(6) cells/ml) at 37 degrees C for 3 hr with various concentrations of micronized Nocodazole or liposome-entrapped Nocodazole were injected i.p. into normal CDF1 mice (10(5) cells/mouse). Longest mean survival times and long-time survivors were observed in the group inoculated with L1210 cells preincubated with liposomes containing Nocodazole. CDF1 mice bearing i.p. or i.v. L1210 leukemia were treated i.p. on days 1, 5 and 9 with micronized or liposome-entrapped Nocodazole. Administration of this latter preparation induced a 50% increase in animal life span at the dosage (25 mg/kg/day) half the one required with the free compound (50 mg/kg/day). The present data indicate that enclosing Nocodazole, a water insoluble antimitotic compound, in liposomes results in an enhanced therapeutic activity against L1210 murine leukemia.

Physicochemical properties of phosphatidylcholine liposomes containing stearylamine

Abstract The influence of stearylamine upon the behavior of unilamellar liposomes formed from dimyristoyl, dipalmitoyl, and distearoyl phosphatidylcholine was investigated. In the presence of stearylamine, optical density measurements indicated that larger liposomal structures are formed. However, when stearylamine was incorporated in distearoyl phosphatidylcholine, i.e., when a stearoyl chain was present in both components of the liposome, no change could be detected. Differential scanning calorimetry of the different liposomal suspensions revealed that for the different systems used, new liposomal structures were formed. The kinetics of transformation depends strongly on the chemical structure of the lipid and of the amine. The possible change in physicochemical properties of the liposome due to the incorporation of a lipid-soluble compound should be kept in mind in any attempt to use liposomes as pharmacological capsules.