betadex and Lung-Diseases

Niemann-Pick type C1 (NPC1) disease arises from a mutation inactivating NPC1 protein that normally moves unesterified cholesterol from the late endosomal/lysosomal complex of cells to the cytosolic compartment for processing. As a result, cholesterol accumulates in every tissue of the body causing liver, lung, and CNS disease. Treatment of the murine model of this disease, the npc1 mouse, s.c. with β-cyclodextrin (4000 mg/kg) one time each week normalized cellular cholesterol metabolism in the liver and most other organs. At the same time, the hepatic dysfunction seen in the untreated npc1 mouse was prevented. The severity of cerebellar neurodegeneration also was ameliorated, although not entirely prevented, and the median lifespan of the animals was doubled. However, in contrast to these other organs, lung showed progressive macrophage infiltration with development of lipoid pneumonitis. These studies demonstrated that weekly cyclodextrin administration overcomes the lysosomal transport defect associated with the NPC1 mutation, nearly normalizes hepatic and whole animal cholesterol pools, and prevents the development of liver disease. Furthermore, this treatment slows cerebellar neurodegeneration but has little or no effect on the development of progressive pulmonary disease.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Anticholesteremic Agents; beta-Cyclodextrins; Biological Transport; Brain; Cholesterol; Disease Models, Animal; Drug Administration Schedule; Injections, Subcutaneous; Intracellular Signaling Peptides and Proteins; Liver; Liver Diseases; Lung; Lung Diseases; Macrophages; Mice; Mice, Inbred BALB C; Mice, Mutant Strains; Mutation; Nerve Degeneration; Niemann-Pick C1 Protein; Niemann-Pick Disease, Type C; Proteins; Time Factors

The inhalation route is widely studied for many drug applications focusing on either local or systemic distributions. One matter of concern is the solubilization of hydrophobic drugs. We have studied the feasibility of using different cyclodextrins (CDs) to elaborate pharmaceutical formulations for the inhalation route and tested the short-term toxicity of such formulations administered by inhalation to C57BL/6 mice. We have shown that HP-beta-CD, gamma-CD, as well as RAMEB aqueous solutions can undergo aerosolization and that the resulting droplet-size ranges are compatible with pulmonary deposition. In vivo, we have demonstrated that short-term exposure to inhaled HP-beta-CD, gamma-CD and RAMEB solutions are non-toxic after assessing bronchoalveolar lavage (BAL), lung and kidney histology, bronchial responsiveness to methacholine and blood urea. The only change noted is a slight increase in lymphocyte count in the BAL after HP-beta-CD and gamma-CD inhalation. We conclude that CDs are useful in significantly enhancing the solubility of apolar drugs with a view to inhalation therapy although an increase in lymphocyte counts in the BAL after CDs inhalations needs further investigations.

Topics: Administration, Inhalation; Aerosols; Animals; beta-Cyclodextrins; Blood Urea Nitrogen; Bronchoalveolar Lavage Fluid; Cell Count; Chemical Phenomena; Chemistry, Pharmaceutical; Chemistry, Physical; Cyclodextrins; Drug Carriers; Excipients; gamma-Cyclodextrins; Inflammation; Kidney; Lung Diseases; Mice; Mice, Inbred C57BL; Nebulizers and Vaporizers; Pharmaceutical Preparations; Surface Tension; Viscosity