R J Debs — Page 3 | PubMed Health

PubMed1987

Successful treatment with aerosolized pentamidine of Pneumocystis carinii pneumonia in rats.

We examined both the therapeutic efficacy and tissue distribution of aerosolized pentamidine in immunosuppressed rats with Pneumocystis carinii pneumonia. In rats immunosuppressed by 5 weeks of pretreatment with dexamethasone, a 2-week course of 5 mg of aerosolized pentamidine per kg per day, administered free or encapsulated in the drug carrier system (liposomes), eradicated P. carinii pneumonia in 75% of treated animals. At this dose, extrapulmonary drug uptake as measured by a sensitive high-pressure liquid chromatography assay was negligible. No significant differences in tissue distribution were noted between aerosolized free and liposome-encapsulated pentamidine. In rats receiving dexamethasone for 6 weeks prior to treatment with pentamidine, both lung uptake and therapeutic efficacy of aerosolized pentamidine (5 mg/kg per day) were substantially reduced. Aerosolized pentamidine appears to be an effective therapy for P. carinii pneumonia in rats and produces significantly lower extrapulmonary drug deposition than parenteral administration. The severity of P. carinii involvement at the time of treatment influences both the level of drug delivery to the lung and the response to aerosolized pentamidine therapy.

Aerosols↗

PubMed1987

Selective enhancement of pentamidine uptake in the lung by aerosolization and delivery in liposomes.

We examined the tissue distribution of pentamidine, both as free drug and encapsulated in liposomes, after intravenous (iv) and aerosol administration in healthy rodents. After iv injection, drug levels in the lung were increased as much as 34-fold by administration in liposomes. Concurrently, peak liver uptake was increased 4-fold and renal deposition reduced 3-fold. Liposome-mediated lung delivery was highly dependent on liposome size. Decreasing liposome mean diameter from 2.5 to 0.4 micron reduced lung uptake of pentamidine 90-fold while affecting extrapulmonary organ deposition to a much lesser degree. Aerosol delivery of pentamidine produced high, sustained lung levels, with no evidence of drug clearance from the lung between 1 and 48 h after administration. Extrapulmonary drug levels produced by aerosol delivery were negligible throughout this period. There were no significant differences in the organ distribution of aerosolized free versus liposome-encapsulated drug, apparently because of sequestration of pentamidine within the lung. Comparison of drug levels in material recovered by bronchoalveolar lavage suggests that aerosol delivery of pentamidine produces substantially higher deposition in the alveolar space than does iv drug injection. Light and electron microscopic (EM) examination of lung, kidney, and liver after iv or aerosol administration of liposomes revealed no tissue abnormalities, although isolated platelet clumps were noted in pulmonary capillaries by EM examination.

Aerosols↗