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1.  Evaluation of novel particles as pulmonary delivery systems for insulin in rats 
AAPS PharmSci  2003;5(2):10-20.
The purpose of the study was to evaluate the influence of calcium phosphate (CAP) and polyethylene glycol (PEG) particles on the systemic delivery of insulin administered by the pulmonary route. Two methods of pulmonary delivery were employed: intratracheal instillation and spray instillation. Insulin-CAP-PEG particles in suspension (1.2 U/kg, 110–140 μL) were administered to the lungs of fasted rats by intratracheal instillation (INCAPEG) or spray instillation (SINCAPEG). Control treatments consisted of insulin solution (1.2 U/kg) by intratracheal instillation, spray instillation, and subcutaneous administration (SC). Plasma concentrations of insulin and glucose were determined by chemiluminescence and colorimetric methods, respectively. Data were analyzed by compartmental and non-compartmental methods, and pharmacokinetic (PK) and pharmacodynamic (PD) parameters of insulin disposition were determined. PK analysis suggested that insulin administered in particles had a longer half-life, a longer mean residence time, and a smaller rate of elimination than insulin in solution. In addition, insulin bioavailability after SINCAPEG was 1.8-fold that of insulin solution administered SC. PD analysis showed that smaller areas under the effect curve and, conversely, larger areas above the effect curve were obtained after INCAPEG in comparison to insulin solution. The magnitude of this effect was increased after SINCAPEG. The presence of CAP-PEG particles appears to positively influence the disposition of insulin administered to the lungs of Sprague-Dawley rats. Spray instillation appears to be a more efficient method of delivering insulin to the lungs of rats than intratracheal instillation.
PMCID: PMC2751517  PMID: 12866936
pulmonary delivery; insulin; CAP-PEG particles; pharmacokinetics; pharmacodynamics
2.  Effect of chloroquine on phagolysosomal fusion in cultured guinea pig alveolar macrophages: Implications in drug delivery 
AAPS PharmSci  2000;2(4):12-18.
The aim of this study was to evaluate the effects of chloroquine on phagolysosomal fusion (PLF) in cultured guinea pig alveolar macrophages (AMs). This technique may be of significance for antitubercular drugs, because the survival of Mycobacterium tuberculosis is linked to evasion of PLF. Guinea pig AMs were obtained from anesthetized animals after exsanguination. The AMs were cultured at a density of 1×106 cell/mL in 24-well plates after attachment to 13-mm coverslips. Culture conditions were at 37°C, with 95% air/5% CO2 in Roswell Park Memorial Institute (RPMI) 1640 medium with 10% heat-inactivated fetal bovine serum. Rhodamine-dextran (70 kd) was incubated with the cells at 0.25 mg/mL for 24 hours to label the lysosomes. Chloroquine treatment where indicated was performed at 10–20 μ g/mL for 1 hour. Fluorescent BioParticles were then added, and PLF was monitored by formation of an organge-yellow fluorescence on fusion of green fluorescent BioParticles with rhodamine-labeled lysosomes. PLF endpoints were measured by scoring for the percentage of orange-yellow cells in the field of view. Image analysis to measure the intensity of the orange-yellow color was performed by obtaining a, b values for 5×5 pixel areas using the Photo Adobe program 4.0.1.
The results indicated that the rate of PLF was enhanced by chloroquine. Thus, chloroquine may be used to potentiate the effects of rifampicin. This may be confirmed by studies involving similar dual fluorophore labeling techniques of fluorescein-labeled formulation in macrophages infected with M. tuberculosis. Preliminary studies with the rhodamine-labeled formulation confirmed cellular uptake and persistence for up to 7 days in culture.
PMCID: PMC2751284  PMID: 11741250
3.  Aerosol delivery of muramyl dipeptide to rodent lungs 
AAPS PharmSci  2000;2(3):53-61.
Tuberculosis is the single most serious infectious disease worldwide. The respiratory tract is the primary site of infection by Mycobacterium tuberculosis (MTB). A number of immunogenic components of the cell wall of MTB, if delivered to the lungs as aerosols, can be used to study the local immune response. The site of deposition of these aerosols can be employed to control their residence time in the lungs. Muramyl dipeptide (MDP) aerosols were delivered to alveolar macrophages in the lungs of rodents. Guinea pig macrophages harvested by bronchoalveolar lavage were examined by differential interference contrast microscopy for morphological changes indicative of activation. Bronchoalveolar lavage fluid was analyzed for the presence of alkaline phosphatase, lactate dehydrogenase, N-acetyl-glucosaminidase (NAG), and total protein content. Rat alveolar macrophages were studied for the production of nitric oxide, by induction of nitric oxide synthase. Twenty-four hours following exposure to an aerosol of MDP, alveolar macrophages exhibited morphological characterstics (spreading and pseudopodia), enzyme activity (NAG 50% above control), and production of the reactive intermediate nitric oxide. Rat macrophages subjected to aerosol exposure to MDP when challenged with a second dose of MDP or lipopolysaccharide exhibited a linear dose response as measured by nitric oxide production. These studies indicate that the topical delivery of an MTB bacterial cell wall component. muramyl dipeptide, results in activation of alveolar macrophages. This approach may be useful in elucidating elements of the immune response to MTB.
PMCID: PMC2761136  PMID: 11741241
Aerosols; Muramyl Dipeptide; Alveolar Macrophages

Results 1-3 (3)