Research ArticlesPharmacokinetic and Pharmacodynamic Evaluation of the Suitability of Using Fluticasone and an Acute Rat Lung Inflammation Model to Differentiate Lung Versus Systemic Efficacy
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INTRODUCTION
Pulmonary diseases, such as chronic obstructive pulmonary disease (COPD) and asthma are complex human airway diseases which affect millions of people worldwide. For example, according to a report from the U.S. Centers for Disease Control and Prevention (CDC), greater than 6% of total American population suffers from asthma in 2004, up from a little over 3% in 1980. Despite the complexity, it is understood that human airway diseases often contain a strong local (lung) inflammatory component. For
Materials
LPS (E. coli O111: B4) was purchased from Sigma–Aldrich (St Louis, MO) and prepared in phosphate buffered saline solution (PBS). Fluticasone propionate was purchased from Seqoia Research Products (Oxford, UK). Microtainer tubes with lithium heparin for blood collection were purchased from Becton Dickinson Biosciences(Franklin Lakes, NJ). 96-well polypropylene plates were purchased from Corning Inc. (Corning, NY). Peri Proneb ultra compression nebulizer was purchased from Peri Co. (Midlothian,
RESULTS AND DISCUSSION
Micronization of fluticasone was successful. The particle size of the bulk material was reduced from a mean value (D50) of 1.6–0.2 µm. The solid form of the micronized material was examined by PXRD and TGA/SDTA without discernable change in crystal form postmicronization process which assured the quality of material used for further PK and PD studies (Fig. 1). Both nano and regular materials were dosed as suspension IT in rat for efficacy and PK studies. Control samples (milled vehicle) were
CONCLUSION
One of the most important qualifiers in searching for better drug candidates for inhalation is to reduce systemic side effects while maintaining efficacy. It is believed that a drug with durable, lung-targeted activity and low systemic exposure would have a theoretical advantage over currently used therapies with improved therapeutic index allowing for higher doses and a better safety profile.
In drug discovery, it is very important to demonstrate preclinical pulmonary targeted efficacy in an
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