Arlene Stecenko

Pulmonary delivery of liposomes

Abstract An overview of current data on pulmonary delivery of liposomes is provided, entailing fate of aerosols in the respiratory tract, physicochemical characterization of liposome aerosols, their therapeutic applications, pulmonary fate and kinetics, and pulmonary safety. Drugs that have been investigated for pulmonary delivery via liposomes include anticancer agents (ara-C), antimicrobials (enviroxime, amikacin, pentamidine), peptides (glutathione), enzymes (superoxide dismutase), antiasthmatic and antiallergic compounds (metaproterenol, salbutamol, cromolyn sodium, corticosteroids). Promising developments including pulmonary delivery of immunomodulators, antiviral agents and gene constructs (cystic fibrosis, α 1 -antitrypsin gene) are also discussed. Finally, pulmonary deposition and kinetics of drugs delivered via liposome aerosols, and targeting strategies to deliver drugs selectively to infected or impaired phagocytic (alveolar macrophages) and nonphagocytic (epithelial) cells in the lung are outlined. Based on the data on therapeutic efficacy and pulmonary safety currently available, we conclude that liposome aerosols may play an important future role in the therapy of pulmonary diseases including intracellular infections, immunologie disorders, and gene defects.

Clinical Pharmacology of Pancreatic Enzymes in Patients with Cystic Fibrosis and In Vitro Performance of Microencapsulated Formulations

Improving protein and fat absorption in patients with cystic fibrosis relates to the amount of biologically active enzyme reaching the duodenum. Microencapsulated formulations are more effective than conventional products but differ in content, ability to retard acid inactivation and the pH at which they release enzymes. Contaminants in these products contribute to hyperuricosuria.

Pulmonary delivery of amikacin liposomes and acute liposome toxicity in the sheep

Although liposome-encapsulated antibiotics designed for intrapulmonary delivery by instillation or aerosolization have been proposed, little is known about the pharmacokinetic profile and toxicity of liposomal drug formulations when delivered to the lung. A technique for large-scale preparation of sterile amikacin liposomes including preparation of a lyophilized amikacin/phospholipid coprecipitate and a highly efficient hollow-fiber dialysis method for rapid removal of unencapsulated drug is described. Doses of 5 and 15 mg/kg amikacin solution or 15 and 45 mg/kg amikacin-containing liposomes consisting of soy phosphatidylcholine/ phosphatidylglycerol (SPC/PG 7:3, molar ratio) or SPC/PG with cholesterol (SPC/PG/CH 4:3:3) were administered intratracheally into intubated, awake sheep. For the 15 mg/kg amikacin solution, the terminal half-life time (t12) was 117 min with maximum plasma levels (cpmax) of 8.3 μg/ml after 2 h and a bioavailability of 38%. The t12 for both doses of amikacin-SPC/PG liposomes was greater than 3 h. Bioavailability varied from 35 to 58%, with a cpmax of 5.5 μg/ml (15 mg/kg) and 23.6 μg/ml (45 mg/kg) after 1.5 h. The t12 of amikacin-SPC/PG/CH liposomes was greater than 10 h with a cpmax of 3.3 μg/ml after 3 h and a bioavailability of 46%. The dosage form was found to be the overall rate-limiting factor for amikacin pharmacokinetics. For assessment of pulmonary function and blood gases, awake sheep inhaled plain liposomes consisting of 15 and 150 mg/ml SPC or hydrogenated SPC (HSPC) for 30 min via a Collision nebulizer. Dynamic compliance (Cdyn), lung resistance (RL), paO2 and paCO2 were analyzed for 6 h post-inhalation (acute effects 0–2 h; delayed effects 2–6 h). All parameters remained within physiologically normal ranges over the entire observation period. It was concluded that liposomes delivered by the pulmonary route act as local sustained release reservoir, and are safe and nonirritating to the lung.

Effect of Passive Smoking on the Lung of Young Lambs

ABSTRACT. The effect of passive smoking on lung histology, lung mechanics, and airway responsiveness (AR) was studied in 2-month-old lambs. Two groups of lambs were studied; 17 were exposed to cigarette smoke (CS) and 13 served as age- and sex-matched controls. Starting at 1 month of age, CS lambs had 25 daily exposures to the smoke generated from eight cigarettes. A smoking machine was constructed for the study using a Bird Ventilator. Two days prior to lung function testing, lambs were anesthetized and a Silastic balloon was placed in the pleural space for later measurement of pleural pressure. At the beginning of each study, lambs were intubated with a nasotracheal tube over a flexible fiberoptic bronchoscope. Lung mechanics (dynamic compliance, resistance of the lung, functional residual capacity) and AR were measured using a whole body plethsymograph. AR to inhaled histamine, carbachol, and citric acid was measured in each lamb on 3 separate days by giving five breaths of increasing concentrations of the aerosol in a noncumulative fashion. AR was measured both within 24 h of the final exposure to CS and at 3–7 days after CS. After the final AR was measured, lambs were anesthetized and an open lung biopsy performed. Control lambs had the same studies as CS lambs performed at an equivalent age. After 25 daily exposures to CS in 17 lambs, mean dynamic compliance was 0.024 ± 0.009 liter/cm H2O, lung resistance was 2.56 ± 1.32 cm H2O·liter−1 s, and functional residual capacity was 0.725 ± 0.234 liter. These values were not significantly different (p > 0.05) from those of the control lambs. Exposure to CS did not significantly change AR to any of the three bronchoprovocation agents tested. Histologic examination of lung tissue showed mild to moderate interstitial mononuclear cellular infiltrate, cellular debris in some airways, and occasional peribronchial inflammation in CS lambs but not in controls. Thus, passive smoking for 1 month in young lambs was not associated with a detectable alteration in lung mechanics or airway responsiveness at a time when inflammatory cells were found in the lung.