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

doi:10.1016/S0277-5379(98)90033-5

European Journal of Cancer and Clinical Oncology

Volume 24, Issue 3, March 1988, Pages 527-538

European Journal of ...

https://doi.org/10.1016/S0277-5379(98)90033-5 Get rights and content

Abstract

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 μg/ml and 5 to 10 μg/ml respectively; while they did not exceed 2 μg/ml and 1 μg/ml with Fungizone®. Amphotericin B given as ampholiposomes had a prolonged serum B 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®.

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The choroid plays an important role in supplying nutrients to and removing waste products from the outer region of the retina. Abnormal choroidal blood flow can disrupt normal retinal function and lead to alterations in visual function. Visualization of the choriocapillaris in vivo is a great challenge to understanding its normal physiology and involvement in the disease process. Laser-targeted angiography (LTA) is a relatively new method used to visualize and analyze the choroidal circulation. Carboxyfluorescein (CF), encapsulated in heat-sensitive liposomes, is released locally in the choroid through the application of a heat beam provided by an infrared laser. Video angiograms are generated with excitation illumination provided by an argon laser. Obtained images are highly selective to the choriocapillaris and are sharply contrasted against underlying and overlying structures. The images can be obtained repetitively, during which period the circulating liposome concentration is sufficient to generate adequate angiograms. These high-quality images have revealed three distinct phases (filling, plateau, and draining) of the choriocapillaris. In the plateau phase, a cluster of lobules fed by a common arteriole has been uniformly illuminated. This defined cluster area does not change in size while an infrared laser is continuously applied to the same spot, which demonstrates that each cluster is functionally independent and no physiological communication exists between them. Only in posterior regions do the angiograms demonstrate during the filling and draining phases that each lobule is filled from a central spot and drained along a peripheral ring, showing honeycomb flow patterns. The regional differences in choriocapillaris flow patterns revealed by LTA suggests that the choriocapillaris provides a more highly efficient system of outflow in posterior regions than in peripheral regions. LTA is useful in analyzing choroidal circulation in vivo and has the potential for clinical application in the future. Additionally, LTA has a unique capability to image choroidal neovascularization in animal models and it promises potential application in age-related macular degeneration (AMD).

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^☆

This work was presented in part at the 22nd meeting of the American Society of Clinical Oncology (Los Angeles, 1986).

This work was supported in part by the ‘Fondation Lefevre’ (Belgium), the Squibb Company (U.S.A.) and the ‘Fonds National de la Recherche Scientifique’ (Belgium).

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

Abstract

Am J Med

J Chromatogr

J Biol Chem

Am J Med

Opportunistic fungal infections in patients with neoplastic disease

Strategies in the treatment of systemic fungal infections

N Engl J Med

Treatment of invasive aspergillosis: relation of early diagnosis and treatment to response

Ann Intern Med

The use of antibiotics

A review of complications of amphotericin B therapy: recommendations for prevention and management

Drug Intel Clin Pharm

Iv administration of a water-insoluble antimitotic compound entrapped in liposomes

Intravenous infusion of high doses of liposomes containing NSC 251635, a water-insoluble cytostatic agent

The limulus test for endotoxin (pyrogen) in radiopharmaceutical biological

Bull Parent Drugs Assoc

Pharmacocinétique, Principes Fondamentaux

A pharmacologic guide to the clinical use of amphotericin B

J Infect Dis

Serum fungistatic and fungicidal activity in volunteers receiving antifungal agents

Eur J Clin Microbiol

Comparing the mean of several groups

N Engl J Med