M. AVIUM DISEASE: INHALED LIPOSOME ANTI-TB DRUG THERAPY. Of the atypical mycobacteria, the Mycobacterium avium-intracellular complex (MAIC) is the most common human pathogen. This facultative intracellular organism escapes killing within alveolar macrophages (AM) and is relatively resistant in vitro to anti-tuberculous drugs such as isoniazid, rifampin, and ethambutol in concentrations currently employed. A major limiting factor for successful therapy of MAIC infections is the high incidence of toxicity from oral administration of clinically more efficacious drugs such as pyrazinamide, ethionamide, and cycloserine. We propose a novel approach to MAIC chemotherapy: Intrapulmonary delivery of drugs encapsulated with liposomes in order to promote their phagocytosis by lung AM. The overall objective of this project is to initiate research that will lead to improved therapy of MAIC infections by formulating lyophilized preparations of liposome-encapsulated antituberculous drugs and studying the feasibility of their delivery via inhalation. The rationale is: (1) inhalation of liposome-encapsulated drugs could be a safer way of delivering these drugs due to confinement of the drug to the infected sites, hence reduction of systemic side effects; (2) liposomes containing drugs could be selectively phagocytized by AM where bacilli reside, thus intracellular MAIC bacillary killing could be enhanced. Consequently, increased therapeutic availability would coincide with reduced toxic availability of these drugs, resulting in an overall improved Therapeutic Index. It is proposed to: (1) encapsulate the drugs pyrazinamide, ethionamide and cycloserine within liposomes of varying physicochemical properties; lyophilize the drug products and assess in vitro stability; (2) assess liposome uptake by AM in vitro by quantitative drug HPLC assay; (3) assess in vitro killing activity of encapsulated vs. unencapsulated drug against MAIC in infected rat AM qualitatively by ultrastructural analysis (TEM) of intracellular degradation of MAIC bacilli and by quantitative cultures (CFU); (4) determine lung and plasma concentrations of liposome- encapsulated drugs following inhalation in rats by HPLC assay; (5) assess effects of chronic liposome inhalation in rats by bronchoalveolar lavage, lung histopathology, autopsy and survival data.
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