Fundamentals of pulmonary drug delivery.

Aerosol administration of peptide-based drugs plays an important role in the treatment of pulmonary and systemic diseases and the unique cellular properties of airway epithelium offers a great potential to deliver new compounds. As the relative contributions from the large airways to the alveolar space are important to the local and systemic availability, the sites and mechanism of uptake and transport of different target compounds have to be characterized. Among the different respiratory cells, the ciliated epithelial cells of the larger and smaller airways and the type I and type II pneumocytes are the key players in pulmonary drug transport. With their diverse cellular characteristics, each of these cell types displays a unique uptake possibility. Next to the knowledge of these cellular aspects, the nature of aerosolized drugs, characteristics of delivery systems and the depositional and pulmonary clearance mechanisms display major targets to optimize pulmonary drug delivery. Based on the growing knowledge on pulmonary cell biology and pathophysiology due to modern methods of molecular biology, the future characterization of pulmonary drug transport pathways can lead to new strategies in aerosol drug therapy.

[1]  M. Neville,et al.  Tight Junction Regulation in the Mammary Gland , 1998, Journal of Mammary Gland Biology and Neoplasia.

[2]  T. Martonen,et al.  Deposition Patterns of Aerosolized Drugs Within Human Lungs: Effects of Ventilatory Parameters , 1993, Pharmaceutical Research.

[3]  T. Martonen,et al.  Behavior of Hygroscopic Pharmaceutical Aerosols and the Influence of Hydrophobic Additives , 2004, Pharmaceutical Research.

[4]  Peter R. Byron,et al.  Comparison of Output Particle Size Distributions from Pressurized Aerosols Formulated as Solutions or Suspensions , 2004, Pharmaceutical Research.

[5]  H. Daniel,et al.  Peptide transport in the mammary gland: expression and distribution of PEPT2 mRNA and protein. , 2002, American journal of physiology. Endocrinology and metabolism.

[6]  A. Nicholson,et al.  Expression of respiratory mucins in fatal status asthmaticus and mild asthma , 2002, Histopathology.

[7]  D. Groneberg,et al.  Leptin receptor expression in nodose ganglion cells projecting to the rat gastric fundus , 2002, Neuroscience Letters.

[8]  M. Klepser,et al.  The Rationale for Aerosolized Antibiotics , 2002, Pharmacotherapy.

[9]  A. Nicholson,et al.  Expression of MUC5AC and MUC5B mucins in normal and cystic fibrosis lung. , 2002, Respiratory medicine.

[10]  K. Chung,et al.  Distribution and function of the peptide transporter PEPT2 in normal and cystic fibrosis human lung , 2002, Thorax.

[11]  D. Groneberg,et al.  Abundant expression of vasoactive intestinal polypeptide receptor VPAC2 mRNA in human skin. , 2001, The Journal of investigative dermatology.

[12]  D. Groneberg,et al.  Intestinal peptide transport: ex vivo uptake studies and localization of peptide carrier PEPT1. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[13]  N. Da,et al.  Hormonal regulation of tight junction closure in the mouse mammary epithelium during the transition from pregnancy to lactation. , 2001 .

[14]  D. Groneberg,et al.  Localization of the peptide transporter PEPT2 in the lung: implications for pulmonary oligopeptide uptake. , 2001, The American journal of pathology.

[15]  M. Neville,et al.  Hormonal regulation of tight junction closure in the mouse mammary epithelium during the transition from pregnancy to lactation. , 2001, The Journal of endocrinology.

[16]  I. Wilding,et al.  Human lung deposition data: the bridge between in vitro and clinical evaluations for inhaled drug products? , 2000, International journal of pharmaceutics.

[17]  I. Adcock,et al.  Expression of heme oxygenase isoenzymes 1 and 2 in normal and asthmatic airways: effect of inhaled corticosteroids. , 2000, American journal of respiratory and critical care medicine.

[18]  D. Klonoff.  Inhaled insulin. , 1999, Diabetes technology & therapeutics.

[19]  P. Thompson.  Drug delivery to the small airways. , 1998, American journal of respiratory and critical care medicine.

[20]  R. Crystal,et al.  Pulmonary cell biology. , 1998, American journal of respiratory and critical care medicine.

[21]  W. Seeger,et al.  Aerosolized Prostacyclin and Iloprost in Severe Pulmonary Hypertension , 1996, Annals of Internal Medicine.

[22]  S. Clarke,et al.  Aerosol delivery systems for bronchial asthma. , 1996, Postgraduate medical journal.

[23]  G. Ferron.  Aerosol properties and lung deposition. , 1994, The European respiratory journal.

[24]  T. Martonen.  Deposition patterns of cigarette smoke in human airways. , 1992, American Industrial Hygiene Association journal.

[25]  Newman Sp.  Aerosol generators and delivery systems. , 1991 .

[26]  S. Newman.  Aerosol generators and delivery systems. , 1991, Respiratory care.

[27]  J. Kaplan,et al.  Fusion of sequentially internalized vesicles in alveolar macrophages , 1990, The Journal of cell biology.

[28]  H. Reynolds,et al.  Macrophages and polymorphonuclear neutrophils in lung defense and injury. , 1990, The American review of respiratory disease.

[29]  R. Rigler,et al.  Laser light scattering spectroscopy: a new method to measure tracheobronchial mucociliary activity. , 1989, Thorax.

[30]  A. Daugherty,et al.  Absorption of human growth hormone from the rat lung. , 1989, Biotechnology therapeutics.

[31]  H. O'brodovich,et al.  Assessment of postmortem respiratory ciliary motility and ultrastructure. , 1987, The American review of respiratory disease.

[32]  K. Ogawa,et al.  Cytochemical quantitation of cytochrome oxidase activity in rat pulmonary alveolar epithelial cells and possible defect in type I cells. , 1986, Journal of electron microscopy.

[33]  J. Vincent,et al.  Kinetics of deposition and clearance of inhaled mineral dusts during chronic exposure. , 1985, British journal of industrial medicine.

[34]  M Dolovich,et al.  Clinical evaluation of a simple demand inhalation MDI aerosol delivery device. , 1983, Chest.

[35]  J. Gil.  Number and distribution of plasmalemmal vesicles in the lung. , 1983, Federation proceedings.

[36]  M. R. Bailey,et al.  The long-term clearance kinetics of insoluble particles from the human lung. , 1982, The Annals of occupational hygiene.

[37]  D. Pavia,et al.  Effects of various inhalation modes on the deposition of radioactive pressurized aerosols. , 1982, European journal of respiratory diseases. Supplement.

[38]  A. Wanner.  Alteration of tracheal mucociliary transport in airway disease. Effect of pharmacologic agents. , 1981, Chest.

[39]  W. B. Johnston,et al.  Static electrification of airborne asbestos: a study of its causes, assessment and effects on deposition in the lungs of rats. , 1981, American Industrial Hygiene Association journal.

[40]  D. Pavia,et al.  How should a pressurized beta-adrenergic bronchodilator be inhaled? , 1981, European journal of respiratory diseases.

[41]  D. Silage,et al.  Distribution of vesicles in cells of air-blood barrier in the rabbit. , 1981, Journal of applied physiology: respiratory, environmental and exercise physiology.

[42]  M. Svartengren,et al.  Retention of particles on the first bifurcation and the trachea of rabbits. , 1981, Bulletin europeen de physiopathologie respiratoire.

[43]  M Lippmann,et al.  Deposition, retention, and clearance of inhaled particles. , 1980, British journal of industrial medicine.

[44]  D. Swift.  Aerosols and humidity therapy. Generation and respiratory deposition of therapeutic aerosols. , 1980, The American review of respiratory disease.

[45]  K. Okumura,et al.  Absorption of insulin delivered to rabbit trachea using aerosol dosage form. , 1979, Journal of pharmaceutical sciences.

[46]  E R Weibel,et al.  Morphometry of the human lung: the state of the art after two decades. , 1979, Bulletin europeen de physiopathologie respiratoire.

[47]  J Yager,et al.  Measurement of frequency of ciliary beats of human respiratory epithelium. , 1978, Chest.

[48]  Chen Tm,et al.  Mucus viscoelasticity and mucociliary transport rate. , 1978 .

[49]  M. J. Dulfano,et al.  Mucus viscoelasticity and mucociliary transport rate. , 1978, The Journal of laboratory and clinical medicine.

[50]  J. Hogg,et al.  Freeze-etch study of the tracheal epithelium of normal guinea pigs with particular reference to intercellular junctions. , 1977, Journal of ultrastructure research.

[51]  T. Stossel.  Phagocytosis. Clinical disorders of recognition and ingestion. , 1977, The American journal of pathology.

[52]  Serafini Sm,et al.  Length and distribution of cilia in human and canine airways. , 1977 .

[53]  J. Baert,et al.  Alveolar clearance and the role of the pulmonary lymphatics. , 1977, The American review of respiratory disease.

[54]  H S Shannon,et al.  Effect of lung function and mode of inhalation on penetration of aerosol into the human lung. , 1977, Thorax.

[55]  M. Lippmann,et al.  Particle deposition in the trachea: in vivo and in hollow casts. , 1976, Thorax.

[56]  J. Hogg,et al.  Zonulae occludentes in alveolar epithelium and capillary endothelium of dog lungs studies with the freeze-fracture technique. , 1976, Journal of ultrastructure research.

[57]  J. Blake,et al.  MECHANICS OF CILIARY LOCOMOTION , 1974, Biological reviews of the Cambridge Philosophical Society.

[58]  J. Baert,et al.  THE ROLE OF THE PULMONARY LYMPHATICS IN THE DEFENSES OF THE DISTAL LUNG: MORPHOLOGICAL AND EXPERIMENTAL STUDIES OF THE TRANSPORT MECHANISMS OF INTRATRACHEALLY INSTILLATED PARTICLES * , 1974, Annals of the New York Academy of Sciences.

[59]  J. Shipp,et al.  Insulin Across Respiratory Mucosae by Aerosol Delivery , 1971, Diabetes.

[60]  S. Sorokin.  Properties of alveolar cells and tissues that strengthen alveolar defenses. , 1970, Archives of internal medicine.

[61]  A E Taylor,et al.  Estimation of equivalent pore radii of pulmonary capillary and alveolar membranes. , 1970, The American journal of physiology.

[62]  M Lippmann,et al.  The effect of particle size on the regional deposition of inhaled aerosols in the human respiratory tract. , 1969, American Industrial Hygiene Association journal.

[63]  J. A. Johnson,et al.  Permeability of the mammalian blood-gas barrier and its components. , 1969, The American journal of physiology.

[64]  B. Holma.  Lung clearance of mono- and di-disperse aerosols determined by profile scanning and whole-body counting. A study on normal and SO2 exposed rabbits. , 1967, Acta medica Scandinavica. Supplementum.

[65]  F. Stiles,et al.  Aerosol therapy in children. , 1953, Wisconsin medical journal.

[66]  F. N. Low.  Electron microscopy of the rat lung , 1952, The Anatomical record.