Chiang, Po-Chang and Hu, Yiding and Blom, Jason D. and Thompson, David C. (2010) Evaluating the Suitability of Using Rat Models for Preclinical Efficacy and Side Effects with Inhaled Corticosteroids Nanosuspension Formulations. NANOSCALE RESEARCH LETTERS, 5 (6). pp. 1010-1019. ISSN 1931-7573 (Print) 1556-276X (Online)
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Official URL: http://www.springerlink.com/content/e6l400g224x437...
Inhaled corticosteroids (ICS) are often prescribed as first-line therapy for patients with asthma Despite their efficacy and improved safety profile compared with oral corticosteroids, the potential for systemic side effects continues to cause concern. In order to reduce the potential for systemic side effects, the pharmaceutical industry has begun efforts to generate new drugs with pulmonary-targeted topical efficacy. One of the major challenges of this approach is to differentiate both efficacy and side effects (pulmonary vs. systemic) in a preclinical animal model. In this study, fluticasone and ciclesonide were used as tool compounds to explore the possibility of demonstrating both efficacy and side effects in a rat model using pulmonary delivery via intratracheal (IT) instillation with nanosuspension formulations. The inhibition of neutrophil infiltration into bronchoalveolar lavage fluid (BALF) and cytokine (TNFÎ±) production were utilized to assess pulmonary efficacy, while adrenal and thymus involution as well as plasma corticosterone suppression was measured to assess systemic side effects. Based on neutrophil infiltration and cytokine production data, the ED50s for ciclesonide and fluticasone were calculated to be 0.1 and 0.03Â mg, respectively. At the ED50, the average adrenal involution was 7.6Â Â±Â 5.3% for ciclesonide versus 16.6Â Â±Â 5.1% for fluticasone, while the average thymus involution was 41.0Â Â±Â 4.3% for ciclesonide versus 59.5Â Â±Â 5.8% for fluticasone. However, the differentiation became less significant when the dose was pushed to the EDmax (0.3Â mg for ciclesonide, 0.1Â mg for fluticasone). Overall, the efficacy and side effect profiles of the two compounds exhibited differentiation at low to mid doses (0.03â0.1Â mg ciclesonide, 0.01â0.03Â mg fluticasone), while this differentiation diminished at the maximum efficacious dose (0.3Â mg ciclesonide, 0.1Â mg fluticasone), likely due to overdosing in this model. We conclude that the rat LPS model using IT administration of nanosuspensions of ICS is a useful tool to demonstrate pulmonary-targeted efficacy and to differentiate the side effects. However, it is only suitable at sub-maximum efficacious levels.
|Subjects:||Biomedical Science > Nanoscale biological processes|
Biomedical Science > Nanotechnology for human health
|Deposited By:||M T V|
|Deposited On:||03 Jun 2010 14:45|
|Last Modified:||03 Jun 2010 14:45|
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