Date of Award:

1992

Document Type:

Thesis

Degree Name:

Master of Science (MS)

Department:

Animal, Dairy, and Veterinary Sciences

Advisor/Chair:

Dr. Stan Allen

Abstract

Because of the increasing number of serious risk factors which predispose a normally immune competent host to infection, the incidence of systemic fungal infections is steadily increasing. This epidemiological rise has especially become apparent since the onset of the AIDS epidemic. Amphotericin B is the drug of choice for these life-threatening mycotic infections. Complications due to drug toxicity, however, severely limit amphotericin B's clinical usefulness. The major complication associated with the administration of amphotericin B is renal toxicity. Research has indicated, however, that besides its antifungal activities, amphotericin B may act as an immune stimulant of both humoral and cellular responses.

A new formulation, liposomal amphotericin B, has been developed which has proven to be significantly less toxic to the kidneys. Research has suggested that liposomal amphotericin B may also act as an immune stimulant. Recent reports have also suggested that its stimulatory capabilities may possibly exceed those of the non-liposomal preparations.

The purpose of this study was to quantify the specific effects of amphotericin B and liposomal amphotericin B on the in vitro indices: cellular viability, B- and T-lymphocyte proliferation and macrophage activation as indicators of immune system functions. Spleen cells from immune normal, and immune compromised BALB/c female mice were harvested following euthanasia and incubated in the presence of the two drugs. Drug doses were chosen to correlate with those surrounding clinically relevant plasma concentrations. Cyclosporine and cyclophosphamide were used as immune suppressants to simulate organ transplant patients and patients receiving cancer chemotherapy, respectively.

Results indicated that amphotericin B consistently reduces the ability of B-cells and T-cells to proliferate and the ability of macrophages to produce interleukin-1. Though direct cytotoxicity may play a part in these assays, it is probably minor because viability studies show no more than a ten percent reduction due to amphotericin B compared with its liposomal analogue.

Liposomal amphotericin B was shown to be non-toxic in each of the immune parameters. It appeared that liposomes may be an important means of delivering more drug to a host infected with a fungal organism without further compromising the patient's already suppressed immune system.

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