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

Abstract

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 drug's 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.

Hemodynamic Changes Induced by Liposomes and Liposome-Encapsulated Hemoglobin in Pigs

“…These studies attest to the general safety of intravenous liposomes, as 4 liposomal drugs entrapping doxorubicin (Doxil), daunorubicin (DaunoXome), and amphotericin B (Abelcet and Ambisome) are already licensed in several countries and many others are in advanced clinical trials. 1 Nevertheless, some of the studies [2][3][4][5][6][7][8][9] have also revealed a hypersensitivity reaction to liposomes that develops immediately after the start of infusion and includes symptoms of cardiopulmonary distress, such as dyspnea, tachypnea, tachycardia, hypotension and hypertension, chest pain, and back pain. Unlike IgE-mediated (type I) allergy, the reaction to liposomes arises at first exposure to the drug without prior sensitization, and the symptoms usually lessen or disappear on later treatments.…”

“…[11][12][13] Nevertheless, complement activation has not been implicated previously in the abovedescribed clinical reactions. [2][3][4][5][6][7][8][9] In an effort to test the hypothesis that complement activation plays a causal role in the cardiopulmonary reaction to intravenous liposomes, we extended here an earlier report from our laboratory on liposome-induced anaphylactoid reaction in miniature pigs. 14 It was suggested in that study that the reaction was due to complement activation; however, direct, conclusive evidence regarding the causal role of complement was not available.…”

Use of Egg Compounds for Cosmetics and Pharmaceutics

“…For example, patients with resistant malignant tumors received 40 intravenous infusions of egg yolk lecithin-based liposomes entrapping a water-insoluble cytostatic agent. But while liposome therapy was very well tolerated, no objective regression of the tumors was observed-although the presence of the drug in the blood was prolonged for 120 hours after its administration (Sculier et al 1986). …”

The possible role of factor H in complement activation-related pseudoallergy (CARPA): a failed attempt to correlate blood levels of FH with liposome-induced hypersensitivity reactions in patients with autoimmune disease

“…These mutations disrupt intrachain disulfide bridges, thereby perturbing the higher order structure of FH. This leads in turn to a profound selective block in secretion of the FH (12). On the other hand, recent studies showed hyperactivation of the alternative C pathway in neuropsychiatric disorders like schizophrenia: single nucleotide polymorphisms (SNPs) of gene encoding FH was found, CFH rs424535 (2783-526T > A) SNP was positively associated with schizophrenia.…”