Aerosolized Pentamidine Rationale And Experimental Animal Studies

Pentamidine is an aromatic diamidine that was initially synthesized in the 1930s in a search for hypoglycemic agents. Because of its antiprotozoal activity, pentamidine has been used extensively for treatment and chemoprophylaxis of African trypanosomiasis. The exact mechanism of action of pentamidine is not known; in vitro, it has been found to interfere with folate metabolism, anaerobic glycolysis, oxidative phosphorylation, and nucleic acid replication [1]. Pentamidine usually is given parenterally in a dose of 4mg/kg/day as the isethionate salt, the only preparation available in the United States [1]. Administration must be parenteral because gastrointestinal absorption is poor. Adverse reactions to pentamidine appear to be dose dependent, in that a 3-g total dose, which usually is reached in the second week of parenteral therapy, frequently causes toxicity [2].

Unlike common prokaryotic pathogens that cause bacterial pneumonia, P. carinii has been a taxomonic enigma. Until recently it was regarded as an extracellular protozoan that inhabits predominantly the alveolar spaces, with close approximation to the surfaces of alveolar epithelial cells and alveolar macrophages [3]. Extrapulmonary P. carinii infections are rare, suggesting that the alveolar environment is usually necessary for growth of the pathogen [3]. More recently P. carinii has been redesignated a fungus [4]. Because of this intra-alveolar location of P. carinii, aerosolization of pentamidine should provide an effective, site-specific, and, hence, less systemically toxic method of therapy or prophylaxis [4]. Studies of aerosolized pentamidine in rats with PCP document efficacy and suggest that the half-life of the drug is long, probably weeks, with increased clearance in ill animals [5-7]. Debs and colleagues [5] reported negligible clearance in 48 hr in normal mice; in rats, the elimination half-life from the lungs may be as long as a month. A study of tissue concentrations after parenteral administration in AIDS patients confirmed that the half-life is long [8].

However, exact alveolar concentrations are unknown because analyses of tissue levels from humans are impractical before death.

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